RARE DISEASE
Audiogenic seizures
Audiogenic seizures
Audiogenic seizures
Drug discovery
1,014
papers
On emerging therapies
Overview
Audiogenic seizures are reflex epileptic events triggered by acoustic stimuli, ranging from simple startle-induced episodes to complex seizures provoked by music or voices. These rare neurological episodes are associated with genetic predispositions and brainstem hyperexcitability, often linked to syndromes like SCN8A encephalopathy. Mortality risk includes sudden unexpected death in epilepsy (SUDEP), particularly in refractory cases [1][2][4][6].
Categories: rare neurological diseases
Research Papers
1,014 drug discovery papers about Audiogenic seizures. Recent publications:
1,014 drug discovery papers about Audiogenic seizures. Recent publications:
categories:
Small molecules
small molecules
2026-08-19 | Cannabidiol In Experimental Epilepsy: A Review of Preclinical Rat Models
Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures and is frequently accompanied by cognitive, behavioral, and psychiatric comorbidities. Despite the availability of numerous antiseizure medications, a substantial proportion of patients remain inadequately controlled, creating a need for therapies with novel mechanisms. Cannabidiol (CBD), a non-intoxicating phytocannabinoid derived from Cannabis sativa, has emerged as a promising antiseizure compound and has subsequently gained regulatory approval for selected developmental and epileptic encephalopathies. This review focuses specifically on preclinical evidence from rat models of epilepsy, emphasizing seizure control, neuroprotection, neuroinflammation, antiepileptogenic effects, pharmacokinetics, and potential mechanisms of action. Studies using pentylenetetrazol (PTZ), pilocarpine, lithium-pilocarpine, kainic acid, audiogenic kindling, and other experimental paradigms demonstrate that CBD can reduce seizure severity, delay seizure onset, decrease seizure burden, and in some models suppress the development or expression of chronic epileptic activity. In rat models of temporal lobe epilepsy, CBD has additionally been associated with reduced neuronal degeneration, modulation of inflammatory cytokines and microglial polarization, changes in PPARγ signaling, and alterations in gut microbiota and metabolomic profiles. Importantly, effects vary with dose, route, treatment timing, model, age, and disease stage. Evidence for genuine antiepileptogenesis remains promising but less established than evidence for acute antiseizure activity. Translation is further complicated by differences in CBD exposure, formulation, metabolism, and pharmacodynamic responses between rodents and humans. Overall, rat studies provide strong mechanistic support for CBD as an antiseizure and potentially neuroprotective agent, but standardized chronic epilepsy protocols, exposure–response studies, sex-balanced designs, rigorous pharmacokinetic–pharmacodynamic characterization, and clinically relevant endpoints are needed to establish its translational value.
2026-08-07 | Anticonvulsant effects, safety, and sex-dependent molecular signatures of cannabidiol treatment in a preclinical model of audiogenic epilepsy
Roughly one-third of patients with epilepsy remain drug resistant, underscoring the need for novel therapeutic strategies. Although cannabidiol (CBD) has recently been approved for specific epileptic encephalopathies, its anticonvulsant mechanisms and the influence of biological sex on treatment response remain incompletely understood. In this preclinical study, we evaluated the efficacy, tolerability, pharmacokinetics, and molecular effects of CBD in the GASH/Sal hamster, a genetic model of audiogenic generalized tonic–clonic seizures. Animals received intraperitoneal CBD (200 mg/kg) either acutely or chronically for 14 days. CBD concentrations were measured in serum and brain, while seizure severity, latency, and neuroethological parameters were assessed following acoustic seizure induction. Safety was evaluated through body weight, hematological, and biochemical analyses, and gene expression profiling was performed in the inferior colliculus, the primary epileptogenic focus. CBD achieved measurable systemic and brain exposure after both acute and chronic administration, despite substantial inter-individual variability and no significant sex differences in drug concentrations. CBD reduced audiogenic seizure severity in a time-dependent manner, with greater protection after chronic treatment. CBD also prolonged latency to seizure onset in both sexes (earlier in females). Although complete seizure suppression was more frequent in females than males (37.5% vs. 12.5% after chronic treatment), direct sex comparisons did not reach statistical significance. Notably, higher serum and brain CBD concentrations were associated with lower seizure severity. Chronic CBD administration was well tolerated in both sexes, affecting selected hematological parameters without altering body weight or liver function. Gene expression profiling revealed that transcriptional organization of the inferior colliculus was driven predominantly by biological sex rather than by seizure induction or CBD treatment. Marked sex-dependent differences were observed in serotonergic, endocannabinoid, purinergic, and Sigmar1-related neuroprotective pathways. Within this molecular context, seizure stimulation modulated Trpv1 and Slc29a1 , whereas chronic CBD induced pathway-specific, sex-dependent changes involving 5-Htr1a , Adora1 , and Cnr1 , without eliciting widespread transcriptional remodeling. Collectively, these findings identify CBD as a well-tolerated anticonvulsant in the GASH/Sal model and suggest that pharmacokinetic exposure and the sex-specific molecular organization of the epileptogenic focus contribute to variability in treatment response, highlighting the importance of considering biological sex in cannabinoid-based epilepsy research.
2026-08-03 | Antiseizure potency and neurotoxicity of the enantiomers of fenfluramine and norfenfluramine in rats and correlations with their concentrations in plasma and brain.
Based on the evidence that fenfluramine-induced anorexia, weight loss, and cardiovascular toxicity are primarily mediated by the d-enantiomers of fenfluramine and its metabolite norfenfluramine, we investigated pharmacokinetic/pharmacodynamic correlations for the active enantiomers of fenfluramine and norfenfluramine in the rat maximal electroshock seizure (MES) test. This is part of a series of studies aimed at optimizing selection of an enantiomerically pure compound for development as a safer alternative to racemic fenfluramine. Median effective concentrations (EC50) in the MES model and median neurotoxic concentrations (TC50) of each enantiomer in plasma and brain were estimated after intraperitoneal administration of d-fenfluramine, l-fenfluramine, and l-norfenfluramine as well as racemates, and compared with the respective median effective (ED50) and neurotoxic (TD50) doses. A newly developed enantioselective assay allowed differentiation of concentrations of each enantiomer after administration of racemates. Protective indexes (PIs) were estimated based on dose (TD50/ED50) and concentration (TC50/EC50) in plasma and brain. Based on ED50, all enantiomers tested had comparable potency, but l-norfenfluramine had a lower PI than the other enantiomers. Based on EC50 in plasma and brain, l-norfenfluramine and d-fenfluramine had the highest potency, but l-norfenfluramine was consistently more toxic than the other enantiomers. The PIs of d-fenfluramine, l-fenfluramine, and l-norfenfluramine were 2.7, 2.4, and 1.2, respectively, based on plasma concentrations, and 4.1, 2.8, and 1.2, respectively, based on brain concentrations. Potency estimates for each enantiomer after dosing with racemic fenfluramine and norfenfluramine were consistently lower than after dosing with the pure enantiomers, indicating that both enantiomers contributed to antiseizure activity. Based on these results, l-fenfluramine has more favorable properties than l-norfenfluramine for potential development as an enantiomerically pure medication. Although our findings are consistent with those previously reported for the MES test in mice and the scn1Lab-/- mutant zebrafish, they differ from those reported for the audiogenic seizures mouse model. Further studies, preferably in disease-specific models, would be desirable.
2026-05-01 | The role of serotonin in post-ictal respiratory recovery and mortality in new models of repeated seizures
Epilepsy is one of the most common neurological disorders, and ~1/3 of patients with epilepsy fail to gain seizure control with anti-seizure medications. These patients are at a particularly high risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is thought to result from post-seizure CNS and cardiorespiratory suppression leading to terminal apnea and asystole. While this general sequence of events in SUDEP is well-documented, the mechanisms by which cardiorespiratory control systems fail after some seizures, but not all seizures, remain elusive. We have previously studied the Dahl Salt-Sensitive Kcnj16-/- rat (SSKcnj16-/-) model, which showed after repeated seizures a progressively greater post-ictal cardiorespiratory suppression, seizure-related mortality, and decreased brainstem serotonin (5-HT) immunoreactivity (-ir) within key brainstem regions of cardiorespiratory control. Here, we tested if additional Kcnj16 mutant rat lines (T64I substitution, AA64-68 deletion (M7), or AA64-81 deletion (M8)) in outbred Sprague-Dawley (SD) rats: 1) repeatedly experience audiogenic seizures, and as a consequence 2) show a progressive ventilatory suppression, seizure-induced mortality, and/or decreased brainstem 5-HT-ir, or 3) if pharmacological depletion of 5-HT with 4-Chloro-DL-phenylalanine (PCPA) promotes seizure-induced death (SzID) in these new models. Ventilation (whole-body plethysmography) and seizure severity (Modified Racine Score; HD video) were quantified in male and female SDKcnj16 mutant lines and wild type (WT) rats for 20 min before (baseline (BL)), during (2-minute auditory stimulus), and up to 20 minutes after seizures, which were induced once daily for up to 10 days. In SDKcnj16 variant animals (T64I; n=15, M7; n=10, and M8; n=12), audiogenic seizures were reproducibly induced daily and led to consistent transient post-ictal respiratory changes without any progressive or cumulative effect. In addition, we did not observe SzID in any of the SDKcnj16 mutant lines and no measurable changes in 5-HT-ir were observed within the nucleus ambiguus (NA) or pre-Bötzinger complex (pre-BötC; T64I; n=4, M7; n=4, and M8; n=4) relative to WT animals (n=4). We next tested if PCPA (200 mg/kg i.p.) or vehicle (equivalent volume of saline) administered before and during the 10-day seizure protocol altered ventilatory responses to seizures and/or induced SzID in SD T64I variants, SD WT, SSKcnj16-/-, and SS WT animals. CNS 5-HT depletion with PCPA was confirmed with HPLC analysis of rat brainstems. Preliminary data suggests that PCPA worsens post-ictal breathing in all Kcnj16 mutant lines regardless of genetic background and hastens mortality in SSKcnj16-/- rats but not SDKcnj16 mutant lines. These studies emphasize the critical role of 5-HT system function in mounting an effective post-ictal cardiorespiratory recovery and survival, but also suggests other factors contribute. Funded by NIH HL122358. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-03-19 | Contribution of astrocytic calcium signaling to auditory hypersensitivity in a mouse model of fragile X syndrome.
Hypersensitivity to sensory stimuli is a common co-morbidity of Fragile X syndrome (FXS), the leading monogenic form of intellectual disability and autism spectrum disorder (ASD). Neuronal impairments associated with auditory and tactile hypersensitivity have been reported in the Fmr1 knockout mouse model of FXS. However, the contribution of astrocytes, in which Fmr1 is also expressed, to sensory hypersensitivity has not been defined. Using mice with astrocyte-specific deletion of Fmr1 (cKO) and mice with astrocyte-specific expression of Fmr1 (cON), we demonstrated that loss of astrocytic FMRP is sufficient but not necessary to confer susceptibility to audiogenic seizures (AGS), an indication of auditory hypersensitivity. Moreover, in vivo multiphoton imaging revealed increased astrocytic calcium signaling in Fmr1 KO mice. To test if enhanced astrocyte calcium signaling contributes to increased AGS, we crossed Fmr1 deletion mice to IP3R2 mutant mice. Reduced expression of IP3R2 rescued the AGS phenotype in the Fmr1 astrocyte cKO but not in the global Fmr1 KO mouse. Our results reveal that astrocytes contribute to AGS in mouse models of FXS through enhanced calcium signaling.
proteins
2026-06-29 | Early life Oxytocin treatment Attenuates Seizure Susceptibility in Male, but not Female, Fmr1-KO Mice.
Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, and is frequently accompanied by seizures. Early-life treatment with the hormone oxytocin (OXT) improves social behavior and cognitive function in rodent models of autism with intellectual disability, including FXS, but potential OXT treatment effects on seizure susceptibility have not been evaluated. Here we tested, in both sexes, if intranasal OXT (iOXT) or saline (iSAL) during the second postnatal week reduces audiogenic seizures (AGS) in the Fmr1-Knockout (KO) mouse model of FXS. OXT given daily from postnatal day (P) 7 to P13 significantly reduced the incidence and severity of AGS and the latency to seize in adult male Fmr1-KOs. Female KOs exhibited less severe seizures that were unaffected by treatment. Wild type mice did not exhibit AGS independent of treatment. To test if antiepileptic effects of iOXT are age-dependent, a separate cohort received iOXT daily from P30 to P36. Male KOs receiving later treatments exhibited robust seizures that were comparable between OXT- and SAL-treatment groups, suggesting that OXT's enduring antiepileptic effects are confined to early postnatal treatments. Tests of acute OXT effects in adulthood demonstrated an attenuation of male Fmr1-KO AGS at testing 30-60 min and 1 day post-treatment but these effects were not evident 15 days later. These findings reveal marked sex differences in the propensity for audiogenic seizures in Fmr1-KO mice and demonstrate that early-life OXT treatment mitigates seizure susceptibility in males FXS model mice.
2026-03-09 | Dysregulated Plasticity in Serotonin, Galanin, and Opioid Systems Contributes to Limbic Seizure Recruitment in Wistar Audiogenic Rat.
The Wistar Audiogenic Rat (WAR) strain is a genetically selected model of reflex epilepsy, susceptible to mesencephalic and, following chronic stimulation, limbic seizures. In this study, we examined the molecular underpinnings of this seizure progression by assessing gene expression profiles of pre-synaptic serotonergic components in Dorsal Raphe Nucleus (DRN) and post-synaptic receptors in the Basolateral Amygdala (BLA), Central Amygdala (CeA), and Hippocampus (HIP). Concurrently, we evaluated mRNA expression of Galanin (Gal) and Prodynorphin (Pdyn) in the Supraoptic Nucleus (SON) and their respective receptors in the BLA, CeA, and HIP. WARs and control Wistar rats underwent a ten-day audiogenic kindling (AK) protocol, involving twice-daily exposure to a high-intensity acoustic stimulus to induce seizures. WARs were sub-grouped based on their behavioral phenotype (seizure scales) into limbic-recruited seizures (LiR) and non-limbic-recruited (n-LiR). Quantitative PCR analysis of brain micropunches revealed a significant failure of adaptive plasticity in WARs. Unlike control rats, which showed a robust upregulation of serotonergic (5-HT-ergic) components in the DRN in response to the chronic stress of the kindling protocol, WARs had a significantly blunted pre-synaptic response. Rats that did not show limbic seizures showed compensatory upregulation of amygdala 5-HT receptors, a mechanism that failed in rats that developed chronic seizures. Furthermore, WARs showed elevated hypothalamic galanin but reduced limbic receptor expression. The opioid system was also imbalanced, with an increase in the pro-convulsant mu-opioid receptor. Critically, Pdyn expression was strongly and negatively correlated with limbic seizure severity. Collectively, these findings suggest that the progression to limbic epilepsy, already demonstrated in behavioral and EEG protocols in this model, is driven by a widespread failure of plasticity across interconnected neuromodulatory networks, rather than a single molecular defect, highlighting novel targets for therapeutic intervention.
2025-01-20 | Epilepsy, compulsion and oxytocin: Insights from behavioral sequences, using neuroethology and complexity systems approaches.
Epilepsies are complex neurological entities usually co-existing with neuropsychiatric comorbidities. We already demonstrated that microinjection of oxytocin (OT) into the central nucleus of amygdala (CeA) induces hypergrooming in Wistar rats, a model of compulsion. Furthermore, the Wistar Audiogenic Rat (WAR) strain is a genetic model of generalized tonic-clonic seizures. Here we quantified grooming behavior in WAR, with grooming scores, flowcharts and directed graphs of syntactic and non-syntactic grooming chains, after bilateral administration of OT or saline (SAL) into the CeA. Our current pioneer behavioral description considers that hypergrooming (compulsion) in WARs is a comorbidity because: (1) WARs have the highest grooming scores, when exposed only to novelty (2), WARs have better grooming scores than Wistars after CeA-SAL, (3) Epileptic WARs perform much better than Wistars in OT-CeA-dependent stereotyped behavioral sequences (flowcharts of syntactic/non-syntactic grooming chains). One additional observation is that the behavioral sequences here demonstrated can be modeled as reliable Markov chains. In conclusion we can drive hypergrooming in WARs, defined previously as a model of ritualistic motor behavior in Wistar rats, with OT from CeA, one of the principal amygdala complex outputs. As perspectives, ongoing cellular studies are on their way, to demonstrate the neural network, certainly incorporating cortico-striatal-thalamic-basal ganglia-cortical circuits, driven from CeA OT-dependent grooming pattern, a stereotyped, sequential and complex array of behaviors, and its association with seizure susceptibility.
2024-08-23 | Repeated seizure-induced brainstem neuroinflammation contributes to post-ictal ventilatory control dysfunction.
Patients with epilepsy face heightened risk of post-ictal cardiorespiratory suppression and sudden unexpected death in epilepsy (SUDEP). Studies have shown that neuroinflammation, mediated by the activation of microglia and astrocytes, may be a cause or consequence of seizure disorders. Kcnj16 (Kir5.1) knockout rats (SS kcnj16-/- ) are susceptible to repeated audiogenic seizures and recapitulate features of human SUDEP, including post-ictal ventilatory suppression, which worsens with repeated seizures and seizure-induced mortality. In this study, we tested the hypothesis that repeated seizures cause neuroinflammation within key brainstem regions that contribute to the control of breathing. Audiogenic seizures were elicited once/day for up to 10 days in groups of adult male SS kcnj16-/- rats, from which frozen brainstem biopsies of the pre-Bötzinger complex/nucleus ambiguus (preBötC/NA), Bötzinger complex (BötC), and raphe magnus (RMg) regions were subjected to a cytokine array. Several cytokines/chemokines, including IL-1α and IL-1ß, were increased selectively in preBötC/NA after 3 or 5 days of seizures with fewer changes in other regions tested. In additional groups of male SS kcnj16-/- rats that underwent repeated seizures, we quantified microglial (IBA-1+) cell counts and morphology, specifically within the preBötC/NA region, and showed increased microglial cell counts, area, and volume consistent with microglial activation. To further test the role of inflammation in physiological responses to seizures and seizure-related mortality, additional groups of SS kcnj16-/- rats were treated with anakinra (IL-1R antagonist), ketoprofen (non-selective COX inhibitor), or saline for 3 days before and up to 10 days of seizures (1/day), and breathing was measured before, during, and after each seizure. Remarkably, IL-1R antagonism mitigated changes in post-ictal ventilatory suppression on days 7-10 but failed to prevent seizure-related mortality, whereas ketoprofen treatment exacerbated post-ictal ventilatory suppression compared to other treatment groups but prevented seizure-related mortality. These data demonstrate neuroinflammation and microglial activation within the key brainstem region of respiratory control following repeated seizures, which may functionally but differentially contribute to the pathophysiological consequences of repeated seizures.
2024-03-28 | P/Q type (Cav2.1) Calcium Channel Blocker ω-Agatoxin IVA Alters Cleaved Caspase-3 and BDNF Expressions in the Rat Brain and Suppresses Seizure Activity.
High-voltage-gated calcium channels have pivot role in the cellular and molecular mechanisms of various neurological disorders, including epilepsy. Similar to other calcium channels, P/Q-type calcium channels (Cav2.1) are also responsible for vesicle release at synaptic terminals. Up to date, there are very limited reports showing the mechanisms of Cav2.1 in epileptogenesis. In the present study, we investigated the anticonvulsive and neuroprotective effects of ω-agatoxin IVA, a specific Cav2.1 blocker, in a chemical kindling model of epileptogenesis. Righting reflex and inclined plane tests were used to assess motor coordination. Electroencephalography was recorded for electrophysiological monitoring of seizure activity in freely moving rats. Immunohistochemical analyses were performed for brain-derived neurotrophic factor (BDNF) and cleaved caspase-3 expressions in the prefrontal cortex, striatum, hippocampus, and thalamic nucleus. ω-Agatoxin IVA injected into the right lateral ventricle significantly prolonged the onset of seizures in a dose-dependent manner. In addition, repeated intraperitoneal administrations of ω-agatoxin IVA significantly suppressed the development of kindling and epileptic discharges without altering motor coordination. In addition, ω-agatoxin IVA significantly increased BDNF expressions, and decreased cleaved caspase-3 expressions in the brain when compared to PTZ + saline group. Our current study emphasizes the significance of the inhibition of P/Q type calcium channels by ω-agatoxin IVA, which suppresses the development of epileptogenesis and provides a new potential pathway for epilepsy treatment.
cell therapies
2026-03-05 | A Review of Vagus Nerve Stimulation for Disease: Comprehensive Theory and Evidence for Mechanisms of Action.
Vagus nerve stimulation (VNS) is an established neuromodulatory therapy approved for epilepsy, depression, obesity, stroke rehabilitation, rheumatoid arthritis, migraine, and cluster headaches. Its therapeutic potential has expanded dramatically, with growing evidence supporting its efficacy across a wide spectrum of neurological, psychiatric, cardiovascular, immunological, metabolic, and gastrointestinal disorders. Despite this progress, the field has lacked a comprehensive synthesis that unifies mechanistic insights with translational applications across organ systems. This review addresses that gap by systematically integrating current knowledge in the multifactorial mechanisms through which VNS modulates central and peripheral functions, including neuromodulator release, synaptic plasticity, autonomic regulation, neuroimmune control, and endocrine integration. In addition, this review identifies key limitations of VNS, including biological heterogeneity, technical constraints, and methodological variability, and proposes future innovations such as selective fiber targeting, closed-loop systems, and artificial intelligence-guided personalization. By providing a rigorous, system-level overview of VNS mechanisms and their translational relevance, this article serves as a foundational resource for advancing the science and clinical deployment and helping illustrate future directions for precision neuromodulation and bioelectronic medicine.
2025-01-30 | Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation.
The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
2022-02-17 | Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention
Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.
2021-08-11 | Amygdala lesions reduce seizure-induced respiratory arrest in DBA/1 mice.
Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Human studies and animal models suggest that respiratory arrest is the initiating event leading to death in many cases of SUDEP. It has previously been reported that the onset of apnea can coincide with the spread of seizures to the amygdala, and apnea can be reproduced by electrical stimulation of the amygdala. The aim of the current work was to determine if the amygdala is required for seizure-induced respiratory arrest (S-IRA) in a mouse model of SUDEP. Experiments were performed on DBA/1 mice that have audiogenic seizures with a high incidence of fatal postictal respiratory arrest. Electrolytic lesions of the amygdala significantly reduced the incidence of S-IRA without altering seizures, baseline breathing, or the hypercapnic ventilatory response. These results indicate that the amygdala is a critical node in a pathway to the lower brainstem that is needed for seizures to cause respiratory arrest. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy is the most common cause of mortality in patients with refractory epilepsy, and S-IRA is thought to be important in the pathophysiology in many cases. In a patient with epilepsy, the onset of apnea has been shown to coincide with spread of seizures to the amygdala, and in multiple patients, apnea was induced by stimulation of the amygdala. Here, we show that lesions of the amygdala reduced the incidence of S-IRA and death in a mouse model of SUDEP. These results provide evidence that the amygdala may be a critical node in the pathway by which seizures influence the brainstem respiratory network to cause apnea. This article is part of the Special Issue NEWroscience 2018.
2020-11-01 | Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development
Abstract Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID‐19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27‐30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2‐deoxy‐D‐glucose, GAO‐3‐02, JNJ‐40411813, NBI‐921352, NTX‐001, sec ‐butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.
gene therapies
2026-06-29 | FMR1 gene therapy restores activity-driven inhibition and prevents audiogenic seizures in Fmr1 -/y mice.
Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with auditory hypersensitivity, circuit hyperexcitability, and seizures. Whether re-expression of the FMR1 gene and encoded Fragile X Messenger Ribonucleoprotein (FMRP) can restore sensory circuit dysfunction remains unclear. Here, we show that a viral AAV-FMR1 vector rescues audiogenic seizures in the Fmr1 -/y mouse model after both neonatal and adult delivery, indicating that auditory circuit dysfunction remains reversible. Local re-expression in the inferior colliculus (IC) is sufficient to reduce seizure susceptibility, identifying this region as a key site of FMRP-dependent circuit regulation. In the IC, Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) profiling reveals impaired induction of sound-evoked translation programs in Fmr1 -/y neurons, including those regulated by transcription factor Npas4. AAV-FMR1 restores a WT-like molecular response and normalizes unbalanced sound-evoked activation of VGLUT2+ excitatory neurons over VGAT+ inhibitory neurons in Fmr1 -/y IC. Together, these findings indicate altered translation of Npas4 in response to sound impairs recruitment of inhibition in the Fmr1 -/y IC, and this can be reversed with AAV-FMR1 administration. Moreover, the rescue of seizures after adult administration of AAV-FMR1 supports a gene therapy approach for FXS.
2025-07-17 | Loss of FMRP in microglia promotes degeneration of parvalbumin neurons and audiogenic seizures via progranulin insufficiency.
Fragile X syndrome (FXS) results from loss of FMR1-encoded FMRP and is associated with reduced density of parvalbumin (PV) neurons; however, the mechanism underlying this abnormality remains unknown. Here we report that microglial FMRP regulates PV neuron density through lysosomal function. Mice with Fmr1 deletion in microglia exhibited audiogenic seizures (AGS) and decreased PV neuron density in the cortex and AGS-associated inferior colliculus (IC). FMRP increased the expression of lysosomal genes in microglia, including the progranulin-encoding Grn gene. Its loss in microglia led to impaired lysosomal function and increased apoptosis in microglia and PV neurons. Furthermore, PV neuron density in the IC was reduced similarly in male Grn +/-, Fmr1 -/y, and Grn +/-;Fmr1 -/y mice, and AAV8-mediated overexpression of progranulin rescued AGS and PV neuron loss in Fmr1 -/y mice. This indicates that progranulin insufficiency is a determinant for PV neuron loss in FXS and elevating progranulin is a therapeutic strategy for FXS.
2022-08-04 | The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures
The high prevalence of diagnosed cases of severe neurological disorders, a significant proportion of which are epilepsy, contributes to a high level of mortality and disability in the population. Neurotrophic factors BDNF and GNDF are considered promising agents aimed at increasing the central nervous system's adaptive potential for the development of the epileptiform activity. Despite the pronounced neuroprotective and anticonvulsant potential, an appropriate way to stimulate these endogenous signaling molecules with minimal risk of side effects remains an open question. Herein, we assessed the safety of gene therapy using original adeno-associated viral constructs carrying the genes of neurotrophic factors BDNF and GDNF in the early postnatal period of development of experimental animals. The intraventricular injection of AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs into newborn mice was found to provide persistent overexpression of target genes in the hippocampus and cerebral cortex in vivo for four weeks after injection. The application of viral constructs has a multidirectional effect on the weight and body length characteristics of mice in the early postnatal period; however, it ensures the animals' resistance to the development of seizure activity under audiogenic stimulation in the late postnatal period and preserves basic behavioral reactions, emotional status, as well as the mnestic and cognitive abilities of mice after simulated stress. Our results demonstrated the safety of using the AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs in vivo, which indicates the expediency of further testing the constructs as therapeutic anticonvulsants.
2021-12-24 | Disruption of synaptic transmission in the Bed Nucleus of the Stria Terminalis reduces seizure-induced death in DBA/1 mice and alters brainstem E/I balance
ABSTRACT Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic and hypoxic ventilatory response. This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of seizure-induced respiratory arrest, potentially through its outputs to brainstem respiratory regions. SUMMARY STATEMENT This study used a viral expression technique to disrupt synaptic output in the bed nucleus of the stria terminalis (BNST) of DBA/1 audiogenic seizure mice. Inactivating the BNST significantly improved survival following seizures and altered brainstem excitation/inhibition balance.
2017-06-01 | Audiogenic seizure activity following HSV-1 GAD65 sense or antisense injection into inferior colliculus of Long–Evans rat
Herpes virus technology involving manipulation of GAD65 was used to study effects on audiogenic seizures (AGS). Audiogenic seizure behaviors were examined following injections of replication-defective herpes simplex virus (HSV-1) vectors incorporating sense or antisense toward GAD65 along with 10% lac-Z into the central nucleus of inferior colliculus (CNIC) of Long–Evans rats. In seizure-sensitive animals developmentally primed by intense sound exposure, injection of GAD65 in the sense orientation increased wild running latencies and reduced incidence of clonus compared with lac-Z only, unoperated, and vehicle seizure groups. In contrast, infection of CNIC with GAD65 antisense virus resulted in 100% incidence of wild running and clonus behaviors in AGS animals. Unprimed animals not operated continued to show uniform absence of seizure activity. Administration of GAD65 antisense virus into CNIC produced novel wild running and clonus behaviors in some unprimed animals. Staining for β-galactosidase in all vector animals revealed no differences in pattern or numbers of immunoreactive cells at injection sites. Qualitatively, typical small and medium multipolar/stellate and medium fusiform neurons appeared in the CNIC of vector animals. These results demonstrate that HSV-1 vector constructs implanted into the CNIC can predictably influence incidence and severity of AGS and suggest that viral vectors can be useful in studying GABA mechanisms with potential for therapeutic application in epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".
other
2026-02-09 | AUDIOGENIC SEIZURE FITS AND POSTICTAL CATALEPSY IN RATS OF KRUSHINSKY–MOLODKINA STRAIN
The main peculiarities are described of rodent audiogenic epilepsy (seizure fits in response to loud sound), which is the complicated trait connected to brain neurochemistry, displaying peculiarities in a range of brain metabolites as well as to the deviations of muscle tone regulation. Selected for audiogenic epilepsy rat strain Krushinsky–Molodkina is the valuable genetic model of human seizure states. The pattern of neurochemical deviations in this strain is similar to those in other rodent strains with audiogenic epilepsy, which permit to suggest the non-random nature of these phenomena. The post-ictal catalepsy and cataleptic states of other groups are discussed in connection with audiogenic seizure fits. Brain anomalies in these animals emerge, presumably, during early ontogeny.
2025-09-01 | Audiogenic Seizures and Postictal Catalepsy in Rats of Krushinsky–Molodkina Strain
The review summarizes the main peculiarities of rodent audiogenic epilepsy (seizures in response to loud sound), which is related to brain neurochemistry and morphology as well as to the disturbances of muscle tone regulation. The Krushinsky–Molodkina rat strain selectively bred for audiogenic epilepsy is the valuable genetic model of human seizure states. The pattern of neurochemical disturbances in this strain is similar to those in other rodent strains with audiogenic epilepsy, which permit to suggest the non-random nature of these phenomena. The postictal catalepsy and cataleptic states of other types are discussed in relation with audiogenic seizure fits. Brain anomalies in these animals emerge, presumably, during early ontogeny.
2025-03-13 | Changes in the Proteomic Profile After Audiogenic Kindling in the Inferior Colliculus of the GASH/Sal Model of Epilepsy.
Epilepsy is a multifaceted neurological disorder characterized by recurrent seizures and associated with molecular and immune alterations in key brain regions. The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca), a genetic model for audiogenic epilepsy, provides a powerful tool to study seizure mechanisms and resistance in predisposed individuals. This study investigates the proteomic and immune responses triggered by audiogenic kindling in the inferior colliculus, comparing non-responder animals exhibiting reduced seizure severity following repeated stimulation versus GASH/Sal naïve hamsters. To assess auditory pathway functionality, Auditory Brainstem Responses (ABRs) were recorded, revealing reduced neuronal activity in the auditory nerve of non-responders, while central auditory processing remained unaffected. Cytokine profiling demonstrated increased levels of proinflammatory markers, including IL-1 alpha (Interleukin-1 alpha), IL-10 (Interleukin-10), and TGF-beta (Transforming Growth Factor beta), alongside decreased IGF-1 (Insulin-like Growth Factor 1) levels, highlighting systemic inflammation and its interplay with neuroprotection. Building on these findings, a proteomic analysis identified 159 differentially expressed proteins (DEPs). Additionally, bioinformatic approaches, including Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), revealed disrupted pathways related to metabolic and inflammatory epileptic processes and a module potentially linked to a rise in the threshold of seizures, respectively. Differentially expressed genes, identified through bioinformatic and statistical analyses, were validated by RT-qPCR. This confirmed the upregulation of six genes (Gpc1-Glypican-1; Sdc3-Syndecan-3; Vgf-Nerve Growth Factor Inducible; Cpne5-Copine 5; Agap2-Arf-GAP with GTPase domain, ANK repeat, and PH domain-containing protein 2; and Dpp8-Dipeptidyl Peptidase 8) and the downregulation of two (Ralb-RAS-like proto-oncogene B-and S100b-S100 calcium-binding protein B), aligning with reduced seizure severity. This study may uncover key proteomic and immune mechanisms underlying seizure susceptibility, providing possible novel therapeutic targets for refractory epilepsy.
2023-08-31 | The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis
Abstract Epilepsy is a neurological disorder that impacts millions of people worldwide, and it is characterized by the occurrence of recurrent seizures. The pathogenesis of epilepsy is complex, involving dysregulation of various genes and signaling pathways. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a vital role in the regulation of gene expression. They have been found to be involved in the pathogenesis of epilepsy, acting as key regulators of neuronal excitability and synaptic plasticity. In recent years, there has been a growing interest in exploring the miRNA regulatory network in epilepsy. This review summarizes the current knowledge of the regulatory miRNAs involved in inflammation and apoptosis in epilepsy and discusses its potential as a new avenue for developing targeted therapies for the treatment of epilepsy.
2021-06-09 | Putative Causal Variant on Vlgr1 for the Epileptic Phenotype in the Model Wistar Audiogenic Rat
Wistar Audiogenic Rat is an epilepsy model whose animals are predisposed to develop seizures induced by acoustic stimulation. This model was developed by selective reproduction and presents a consistent genetic profile due to the several generations of inbreeding. In this study, we performed an analysis of WAR RNA-Seq data, aiming identified at genetic variants that may be involved in the epileptic phenotype. Seventeen thousand eighty-five predicted variants were identified as unique to the WAR model, of which 15,915 variants are SNPs and 1,170 INDELs. We filter the predicted variants by pre-established criteria and selected five for validation by Sanger sequencing. The genetic variant c.14198T>C in the Vlgr1 gene was confirmed in the WAR model. Vlgr1 encodes an adhesion receptor that is involved in the myelination process, in the development of stereocilia of the inner ear, and was already associated with the audiogenic seizures presented by the mice Frings. The transcriptional quantification of Vlgr1 revealed the downregulation this gene in the corpus quadrigeminum of WAR, and the protein modeling predicted that the mutated residue alters the structure of a domain of the VLGR1 receptor. We believe that Vlgr1 gene may be related to the predisposition of WAR to seizures and suggest the mutation Vlgr1 /Q4695R as putative causal variant, and the first molecular marker of the WAR strain.
small molecules
2026-08-19 | Cannabidiol In Experimental Epilepsy: A Review of Preclinical Rat Models
Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures and is frequently accompanied by cognitive, behavioral, and psychiatric comorbidities. Despite the availability of numerous antiseizure medications, a substantial proportion of patients remain inadequately controlled, creating a need for therapies with novel mechanisms. Cannabidiol (CBD), a non-intoxicating phytocannabinoid derived from Cannabis sativa, has emerged as a promising antiseizure compound and has subsequently gained regulatory approval for selected developmental and epileptic encephalopathies. This review focuses specifically on preclinical evidence from rat models of epilepsy, emphasizing seizure control, neuroprotection, neuroinflammation, antiepileptogenic effects, pharmacokinetics, and potential mechanisms of action. Studies using pentylenetetrazol (PTZ), pilocarpine, lithium-pilocarpine, kainic acid, audiogenic kindling, and other experimental paradigms demonstrate that CBD can reduce seizure severity, delay seizure onset, decrease seizure burden, and in some models suppress the development or expression of chronic epileptic activity. In rat models of temporal lobe epilepsy, CBD has additionally been associated with reduced neuronal degeneration, modulation of inflammatory cytokines and microglial polarization, changes in PPARγ signaling, and alterations in gut microbiota and metabolomic profiles. Importantly, effects vary with dose, route, treatment timing, model, age, and disease stage. Evidence for genuine antiepileptogenesis remains promising but less established than evidence for acute antiseizure activity. Translation is further complicated by differences in CBD exposure, formulation, metabolism, and pharmacodynamic responses between rodents and humans. Overall, rat studies provide strong mechanistic support for CBD as an antiseizure and potentially neuroprotective agent, but standardized chronic epilepsy protocols, exposure–response studies, sex-balanced designs, rigorous pharmacokinetic–pharmacodynamic characterization, and clinically relevant endpoints are needed to establish its translational value.
2026-08-07 | Anticonvulsant effects, safety, and sex-dependent molecular signatures of cannabidiol treatment in a preclinical model of audiogenic epilepsy
Roughly one-third of patients with epilepsy remain drug resistant, underscoring the need for novel therapeutic strategies. Although cannabidiol (CBD) has recently been approved for specific epileptic encephalopathies, its anticonvulsant mechanisms and the influence of biological sex on treatment response remain incompletely understood. In this preclinical study, we evaluated the efficacy, tolerability, pharmacokinetics, and molecular effects of CBD in the GASH/Sal hamster, a genetic model of audiogenic generalized tonic–clonic seizures. Animals received intraperitoneal CBD (200 mg/kg) either acutely or chronically for 14 days. CBD concentrations were measured in serum and brain, while seizure severity, latency, and neuroethological parameters were assessed following acoustic seizure induction. Safety was evaluated through body weight, hematological, and biochemical analyses, and gene expression profiling was performed in the inferior colliculus, the primary epileptogenic focus. CBD achieved measurable systemic and brain exposure after both acute and chronic administration, despite substantial inter-individual variability and no significant sex differences in drug concentrations. CBD reduced audiogenic seizure severity in a time-dependent manner, with greater protection after chronic treatment. CBD also prolonged latency to seizure onset in both sexes (earlier in females). Although complete seizure suppression was more frequent in females than males (37.5% vs. 12.5% after chronic treatment), direct sex comparisons did not reach statistical significance. Notably, higher serum and brain CBD concentrations were associated with lower seizure severity. Chronic CBD administration was well tolerated in both sexes, affecting selected hematological parameters without altering body weight or liver function. Gene expression profiling revealed that transcriptional organization of the inferior colliculus was driven predominantly by biological sex rather than by seizure induction or CBD treatment. Marked sex-dependent differences were observed in serotonergic, endocannabinoid, purinergic, and Sigmar1-related neuroprotective pathways. Within this molecular context, seizure stimulation modulated Trpv1 and Slc29a1 , whereas chronic CBD induced pathway-specific, sex-dependent changes involving 5-Htr1a , Adora1 , and Cnr1 , without eliciting widespread transcriptional remodeling. Collectively, these findings identify CBD as a well-tolerated anticonvulsant in the GASH/Sal model and suggest that pharmacokinetic exposure and the sex-specific molecular organization of the epileptogenic focus contribute to variability in treatment response, highlighting the importance of considering biological sex in cannabinoid-based epilepsy research.
2026-08-03 | Antiseizure potency and neurotoxicity of the enantiomers of fenfluramine and norfenfluramine in rats and correlations with their concentrations in plasma and brain.
Based on the evidence that fenfluramine-induced anorexia, weight loss, and cardiovascular toxicity are primarily mediated by the d-enantiomers of fenfluramine and its metabolite norfenfluramine, we investigated pharmacokinetic/pharmacodynamic correlations for the active enantiomers of fenfluramine and norfenfluramine in the rat maximal electroshock seizure (MES) test. This is part of a series of studies aimed at optimizing selection of an enantiomerically pure compound for development as a safer alternative to racemic fenfluramine. Median effective concentrations (EC50) in the MES model and median neurotoxic concentrations (TC50) of each enantiomer in plasma and brain were estimated after intraperitoneal administration of d-fenfluramine, l-fenfluramine, and l-norfenfluramine as well as racemates, and compared with the respective median effective (ED50) and neurotoxic (TD50) doses. A newly developed enantioselective assay allowed differentiation of concentrations of each enantiomer after administration of racemates. Protective indexes (PIs) were estimated based on dose (TD50/ED50) and concentration (TC50/EC50) in plasma and brain. Based on ED50, all enantiomers tested had comparable potency, but l-norfenfluramine had a lower PI than the other enantiomers. Based on EC50 in plasma and brain, l-norfenfluramine and d-fenfluramine had the highest potency, but l-norfenfluramine was consistently more toxic than the other enantiomers. The PIs of d-fenfluramine, l-fenfluramine, and l-norfenfluramine were 2.7, 2.4, and 1.2, respectively, based on plasma concentrations, and 4.1, 2.8, and 1.2, respectively, based on brain concentrations. Potency estimates for each enantiomer after dosing with racemic fenfluramine and norfenfluramine were consistently lower than after dosing with the pure enantiomers, indicating that both enantiomers contributed to antiseizure activity. Based on these results, l-fenfluramine has more favorable properties than l-norfenfluramine for potential development as an enantiomerically pure medication. Although our findings are consistent with those previously reported for the MES test in mice and the scn1Lab-/- mutant zebrafish, they differ from those reported for the audiogenic seizures mouse model. Further studies, preferably in disease-specific models, would be desirable.
2026-05-01 | The role of serotonin in post-ictal respiratory recovery and mortality in new models of repeated seizures
Epilepsy is one of the most common neurological disorders, and ~1/3 of patients with epilepsy fail to gain seizure control with anti-seizure medications. These patients are at a particularly high risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is thought to result from post-seizure CNS and cardiorespiratory suppression leading to terminal apnea and asystole. While this general sequence of events in SUDEP is well-documented, the mechanisms by which cardiorespiratory control systems fail after some seizures, but not all seizures, remain elusive. We have previously studied the Dahl Salt-Sensitive Kcnj16-/- rat (SSKcnj16-/-) model, which showed after repeated seizures a progressively greater post-ictal cardiorespiratory suppression, seizure-related mortality, and decreased brainstem serotonin (5-HT) immunoreactivity (-ir) within key brainstem regions of cardiorespiratory control. Here, we tested if additional Kcnj16 mutant rat lines (T64I substitution, AA64-68 deletion (M7), or AA64-81 deletion (M8)) in outbred Sprague-Dawley (SD) rats: 1) repeatedly experience audiogenic seizures, and as a consequence 2) show a progressive ventilatory suppression, seizure-induced mortality, and/or decreased brainstem 5-HT-ir, or 3) if pharmacological depletion of 5-HT with 4-Chloro-DL-phenylalanine (PCPA) promotes seizure-induced death (SzID) in these new models. Ventilation (whole-body plethysmography) and seizure severity (Modified Racine Score; HD video) were quantified in male and female SDKcnj16 mutant lines and wild type (WT) rats for 20 min before (baseline (BL)), during (2-minute auditory stimulus), and up to 20 minutes after seizures, which were induced once daily for up to 10 days. In SDKcnj16 variant animals (T64I; n=15, M7; n=10, and M8; n=12), audiogenic seizures were reproducibly induced daily and led to consistent transient post-ictal respiratory changes without any progressive or cumulative effect. In addition, we did not observe SzID in any of the SDKcnj16 mutant lines and no measurable changes in 5-HT-ir were observed within the nucleus ambiguus (NA) or pre-Bötzinger complex (pre-BötC; T64I; n=4, M7; n=4, and M8; n=4) relative to WT animals (n=4). We next tested if PCPA (200 mg/kg i.p.) or vehicle (equivalent volume of saline) administered before and during the 10-day seizure protocol altered ventilatory responses to seizures and/or induced SzID in SD T64I variants, SD WT, SSKcnj16-/-, and SS WT animals. CNS 5-HT depletion with PCPA was confirmed with HPLC analysis of rat brainstems. Preliminary data suggests that PCPA worsens post-ictal breathing in all Kcnj16 mutant lines regardless of genetic background and hastens mortality in SSKcnj16-/- rats but not SDKcnj16 mutant lines. These studies emphasize the critical role of 5-HT system function in mounting an effective post-ictal cardiorespiratory recovery and survival, but also suggests other factors contribute. Funded by NIH HL122358. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-03-19 | Contribution of astrocytic calcium signaling to auditory hypersensitivity in a mouse model of fragile X syndrome.
Hypersensitivity to sensory stimuli is a common co-morbidity of Fragile X syndrome (FXS), the leading monogenic form of intellectual disability and autism spectrum disorder (ASD). Neuronal impairments associated with auditory and tactile hypersensitivity have been reported in the Fmr1 knockout mouse model of FXS. However, the contribution of astrocytes, in which Fmr1 is also expressed, to sensory hypersensitivity has not been defined. Using mice with astrocyte-specific deletion of Fmr1 (cKO) and mice with astrocyte-specific expression of Fmr1 (cON), we demonstrated that loss of astrocytic FMRP is sufficient but not necessary to confer susceptibility to audiogenic seizures (AGS), an indication of auditory hypersensitivity. Moreover, in vivo multiphoton imaging revealed increased astrocytic calcium signaling in Fmr1 KO mice. To test if enhanced astrocyte calcium signaling contributes to increased AGS, we crossed Fmr1 deletion mice to IP3R2 mutant mice. Reduced expression of IP3R2 rescued the AGS phenotype in the Fmr1 astrocyte cKO but not in the global Fmr1 KO mouse. Our results reveal that astrocytes contribute to AGS in mouse models of FXS through enhanced calcium signaling.
proteins
2026-06-29 | Early life Oxytocin treatment Attenuates Seizure Susceptibility in Male, but not Female, Fmr1-KO Mice.
Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, and is frequently accompanied by seizures. Early-life treatment with the hormone oxytocin (OXT) improves social behavior and cognitive function in rodent models of autism with intellectual disability, including FXS, but potential OXT treatment effects on seizure susceptibility have not been evaluated. Here we tested, in both sexes, if intranasal OXT (iOXT) or saline (iSAL) during the second postnatal week reduces audiogenic seizures (AGS) in the Fmr1-Knockout (KO) mouse model of FXS. OXT given daily from postnatal day (P) 7 to P13 significantly reduced the incidence and severity of AGS and the latency to seize in adult male Fmr1-KOs. Female KOs exhibited less severe seizures that were unaffected by treatment. Wild type mice did not exhibit AGS independent of treatment. To test if antiepileptic effects of iOXT are age-dependent, a separate cohort received iOXT daily from P30 to P36. Male KOs receiving later treatments exhibited robust seizures that were comparable between OXT- and SAL-treatment groups, suggesting that OXT's enduring antiepileptic effects are confined to early postnatal treatments. Tests of acute OXT effects in adulthood demonstrated an attenuation of male Fmr1-KO AGS at testing 30-60 min and 1 day post-treatment but these effects were not evident 15 days later. These findings reveal marked sex differences in the propensity for audiogenic seizures in Fmr1-KO mice and demonstrate that early-life OXT treatment mitigates seizure susceptibility in males FXS model mice.
2026-03-09 | Dysregulated Plasticity in Serotonin, Galanin, and Opioid Systems Contributes to Limbic Seizure Recruitment in Wistar Audiogenic Rat.
The Wistar Audiogenic Rat (WAR) strain is a genetically selected model of reflex epilepsy, susceptible to mesencephalic and, following chronic stimulation, limbic seizures. In this study, we examined the molecular underpinnings of this seizure progression by assessing gene expression profiles of pre-synaptic serotonergic components in Dorsal Raphe Nucleus (DRN) and post-synaptic receptors in the Basolateral Amygdala (BLA), Central Amygdala (CeA), and Hippocampus (HIP). Concurrently, we evaluated mRNA expression of Galanin (Gal) and Prodynorphin (Pdyn) in the Supraoptic Nucleus (SON) and their respective receptors in the BLA, CeA, and HIP. WARs and control Wistar rats underwent a ten-day audiogenic kindling (AK) protocol, involving twice-daily exposure to a high-intensity acoustic stimulus to induce seizures. WARs were sub-grouped based on their behavioral phenotype (seizure scales) into limbic-recruited seizures (LiR) and non-limbic-recruited (n-LiR). Quantitative PCR analysis of brain micropunches revealed a significant failure of adaptive plasticity in WARs. Unlike control rats, which showed a robust upregulation of serotonergic (5-HT-ergic) components in the DRN in response to the chronic stress of the kindling protocol, WARs had a significantly blunted pre-synaptic response. Rats that did not show limbic seizures showed compensatory upregulation of amygdala 5-HT receptors, a mechanism that failed in rats that developed chronic seizures. Furthermore, WARs showed elevated hypothalamic galanin but reduced limbic receptor expression. The opioid system was also imbalanced, with an increase in the pro-convulsant mu-opioid receptor. Critically, Pdyn expression was strongly and negatively correlated with limbic seizure severity. Collectively, these findings suggest that the progression to limbic epilepsy, already demonstrated in behavioral and EEG protocols in this model, is driven by a widespread failure of plasticity across interconnected neuromodulatory networks, rather than a single molecular defect, highlighting novel targets for therapeutic intervention.
2025-01-20 | Epilepsy, compulsion and oxytocin: Insights from behavioral sequences, using neuroethology and complexity systems approaches.
Epilepsies are complex neurological entities usually co-existing with neuropsychiatric comorbidities. We already demonstrated that microinjection of oxytocin (OT) into the central nucleus of amygdala (CeA) induces hypergrooming in Wistar rats, a model of compulsion. Furthermore, the Wistar Audiogenic Rat (WAR) strain is a genetic model of generalized tonic-clonic seizures. Here we quantified grooming behavior in WAR, with grooming scores, flowcharts and directed graphs of syntactic and non-syntactic grooming chains, after bilateral administration of OT or saline (SAL) into the CeA. Our current pioneer behavioral description considers that hypergrooming (compulsion) in WARs is a comorbidity because: (1) WARs have the highest grooming scores, when exposed only to novelty (2), WARs have better grooming scores than Wistars after CeA-SAL, (3) Epileptic WARs perform much better than Wistars in OT-CeA-dependent stereotyped behavioral sequences (flowcharts of syntactic/non-syntactic grooming chains). One additional observation is that the behavioral sequences here demonstrated can be modeled as reliable Markov chains. In conclusion we can drive hypergrooming in WARs, defined previously as a model of ritualistic motor behavior in Wistar rats, with OT from CeA, one of the principal amygdala complex outputs. As perspectives, ongoing cellular studies are on their way, to demonstrate the neural network, certainly incorporating cortico-striatal-thalamic-basal ganglia-cortical circuits, driven from CeA OT-dependent grooming pattern, a stereotyped, sequential and complex array of behaviors, and its association with seizure susceptibility.
2024-08-23 | Repeated seizure-induced brainstem neuroinflammation contributes to post-ictal ventilatory control dysfunction.
Patients with epilepsy face heightened risk of post-ictal cardiorespiratory suppression and sudden unexpected death in epilepsy (SUDEP). Studies have shown that neuroinflammation, mediated by the activation of microglia and astrocytes, may be a cause or consequence of seizure disorders. Kcnj16 (Kir5.1) knockout rats (SS kcnj16-/- ) are susceptible to repeated audiogenic seizures and recapitulate features of human SUDEP, including post-ictal ventilatory suppression, which worsens with repeated seizures and seizure-induced mortality. In this study, we tested the hypothesis that repeated seizures cause neuroinflammation within key brainstem regions that contribute to the control of breathing. Audiogenic seizures were elicited once/day for up to 10 days in groups of adult male SS kcnj16-/- rats, from which frozen brainstem biopsies of the pre-Bötzinger complex/nucleus ambiguus (preBötC/NA), Bötzinger complex (BötC), and raphe magnus (RMg) regions were subjected to a cytokine array. Several cytokines/chemokines, including IL-1α and IL-1ß, were increased selectively in preBötC/NA after 3 or 5 days of seizures with fewer changes in other regions tested. In additional groups of male SS kcnj16-/- rats that underwent repeated seizures, we quantified microglial (IBA-1+) cell counts and morphology, specifically within the preBötC/NA region, and showed increased microglial cell counts, area, and volume consistent with microglial activation. To further test the role of inflammation in physiological responses to seizures and seizure-related mortality, additional groups of SS kcnj16-/- rats were treated with anakinra (IL-1R antagonist), ketoprofen (non-selective COX inhibitor), or saline for 3 days before and up to 10 days of seizures (1/day), and breathing was measured before, during, and after each seizure. Remarkably, IL-1R antagonism mitigated changes in post-ictal ventilatory suppression on days 7-10 but failed to prevent seizure-related mortality, whereas ketoprofen treatment exacerbated post-ictal ventilatory suppression compared to other treatment groups but prevented seizure-related mortality. These data demonstrate neuroinflammation and microglial activation within the key brainstem region of respiratory control following repeated seizures, which may functionally but differentially contribute to the pathophysiological consequences of repeated seizures.
2024-03-28 | P/Q type (Cav2.1) Calcium Channel Blocker ω-Agatoxin IVA Alters Cleaved Caspase-3 and BDNF Expressions in the Rat Brain and Suppresses Seizure Activity.
High-voltage-gated calcium channels have pivot role in the cellular and molecular mechanisms of various neurological disorders, including epilepsy. Similar to other calcium channels, P/Q-type calcium channels (Cav2.1) are also responsible for vesicle release at synaptic terminals. Up to date, there are very limited reports showing the mechanisms of Cav2.1 in epileptogenesis. In the present study, we investigated the anticonvulsive and neuroprotective effects of ω-agatoxin IVA, a specific Cav2.1 blocker, in a chemical kindling model of epileptogenesis. Righting reflex and inclined plane tests were used to assess motor coordination. Electroencephalography was recorded for electrophysiological monitoring of seizure activity in freely moving rats. Immunohistochemical analyses were performed for brain-derived neurotrophic factor (BDNF) and cleaved caspase-3 expressions in the prefrontal cortex, striatum, hippocampus, and thalamic nucleus. ω-Agatoxin IVA injected into the right lateral ventricle significantly prolonged the onset of seizures in a dose-dependent manner. In addition, repeated intraperitoneal administrations of ω-agatoxin IVA significantly suppressed the development of kindling and epileptic discharges without altering motor coordination. In addition, ω-agatoxin IVA significantly increased BDNF expressions, and decreased cleaved caspase-3 expressions in the brain when compared to PTZ + saline group. Our current study emphasizes the significance of the inhibition of P/Q type calcium channels by ω-agatoxin IVA, which suppresses the development of epileptogenesis and provides a new potential pathway for epilepsy treatment.
cell therapies
2026-03-05 | A Review of Vagus Nerve Stimulation for Disease: Comprehensive Theory and Evidence for Mechanisms of Action.
Vagus nerve stimulation (VNS) is an established neuromodulatory therapy approved for epilepsy, depression, obesity, stroke rehabilitation, rheumatoid arthritis, migraine, and cluster headaches. Its therapeutic potential has expanded dramatically, with growing evidence supporting its efficacy across a wide spectrum of neurological, psychiatric, cardiovascular, immunological, metabolic, and gastrointestinal disorders. Despite this progress, the field has lacked a comprehensive synthesis that unifies mechanistic insights with translational applications across organ systems. This review addresses that gap by systematically integrating current knowledge in the multifactorial mechanisms through which VNS modulates central and peripheral functions, including neuromodulator release, synaptic plasticity, autonomic regulation, neuroimmune control, and endocrine integration. In addition, this review identifies key limitations of VNS, including biological heterogeneity, technical constraints, and methodological variability, and proposes future innovations such as selective fiber targeting, closed-loop systems, and artificial intelligence-guided personalization. By providing a rigorous, system-level overview of VNS mechanisms and their translational relevance, this article serves as a foundational resource for advancing the science and clinical deployment and helping illustrate future directions for precision neuromodulation and bioelectronic medicine.
2025-01-30 | Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation.
The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
2022-02-17 | Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention
Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.
2021-08-11 | Amygdala lesions reduce seizure-induced respiratory arrest in DBA/1 mice.
Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Human studies and animal models suggest that respiratory arrest is the initiating event leading to death in many cases of SUDEP. It has previously been reported that the onset of apnea can coincide with the spread of seizures to the amygdala, and apnea can be reproduced by electrical stimulation of the amygdala. The aim of the current work was to determine if the amygdala is required for seizure-induced respiratory arrest (S-IRA) in a mouse model of SUDEP. Experiments were performed on DBA/1 mice that have audiogenic seizures with a high incidence of fatal postictal respiratory arrest. Electrolytic lesions of the amygdala significantly reduced the incidence of S-IRA without altering seizures, baseline breathing, or the hypercapnic ventilatory response. These results indicate that the amygdala is a critical node in a pathway to the lower brainstem that is needed for seizures to cause respiratory arrest. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy is the most common cause of mortality in patients with refractory epilepsy, and S-IRA is thought to be important in the pathophysiology in many cases. In a patient with epilepsy, the onset of apnea has been shown to coincide with spread of seizures to the amygdala, and in multiple patients, apnea was induced by stimulation of the amygdala. Here, we show that lesions of the amygdala reduced the incidence of S-IRA and death in a mouse model of SUDEP. These results provide evidence that the amygdala may be a critical node in the pathway by which seizures influence the brainstem respiratory network to cause apnea. This article is part of the Special Issue NEWroscience 2018.
2020-11-01 | Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development
Abstract Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID‐19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27‐30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2‐deoxy‐D‐glucose, GAO‐3‐02, JNJ‐40411813, NBI‐921352, NTX‐001, sec ‐butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.
gene therapies
2026-06-29 | FMR1 gene therapy restores activity-driven inhibition and prevents audiogenic seizures in Fmr1 -/y mice.
Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with auditory hypersensitivity, circuit hyperexcitability, and seizures. Whether re-expression of the FMR1 gene and encoded Fragile X Messenger Ribonucleoprotein (FMRP) can restore sensory circuit dysfunction remains unclear. Here, we show that a viral AAV-FMR1 vector rescues audiogenic seizures in the Fmr1 -/y mouse model after both neonatal and adult delivery, indicating that auditory circuit dysfunction remains reversible. Local re-expression in the inferior colliculus (IC) is sufficient to reduce seizure susceptibility, identifying this region as a key site of FMRP-dependent circuit regulation. In the IC, Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) profiling reveals impaired induction of sound-evoked translation programs in Fmr1 -/y neurons, including those regulated by transcription factor Npas4. AAV-FMR1 restores a WT-like molecular response and normalizes unbalanced sound-evoked activation of VGLUT2+ excitatory neurons over VGAT+ inhibitory neurons in Fmr1 -/y IC. Together, these findings indicate altered translation of Npas4 in response to sound impairs recruitment of inhibition in the Fmr1 -/y IC, and this can be reversed with AAV-FMR1 administration. Moreover, the rescue of seizures after adult administration of AAV-FMR1 supports a gene therapy approach for FXS.
2025-07-17 | Loss of FMRP in microglia promotes degeneration of parvalbumin neurons and audiogenic seizures via progranulin insufficiency.
Fragile X syndrome (FXS) results from loss of FMR1-encoded FMRP and is associated with reduced density of parvalbumin (PV) neurons; however, the mechanism underlying this abnormality remains unknown. Here we report that microglial FMRP regulates PV neuron density through lysosomal function. Mice with Fmr1 deletion in microglia exhibited audiogenic seizures (AGS) and decreased PV neuron density in the cortex and AGS-associated inferior colliculus (IC). FMRP increased the expression of lysosomal genes in microglia, including the progranulin-encoding Grn gene. Its loss in microglia led to impaired lysosomal function and increased apoptosis in microglia and PV neurons. Furthermore, PV neuron density in the IC was reduced similarly in male Grn +/-, Fmr1 -/y, and Grn +/-;Fmr1 -/y mice, and AAV8-mediated overexpression of progranulin rescued AGS and PV neuron loss in Fmr1 -/y mice. This indicates that progranulin insufficiency is a determinant for PV neuron loss in FXS and elevating progranulin is a therapeutic strategy for FXS.
2022-08-04 | The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures
The high prevalence of diagnosed cases of severe neurological disorders, a significant proportion of which are epilepsy, contributes to a high level of mortality and disability in the population. Neurotrophic factors BDNF and GNDF are considered promising agents aimed at increasing the central nervous system's adaptive potential for the development of the epileptiform activity. Despite the pronounced neuroprotective and anticonvulsant potential, an appropriate way to stimulate these endogenous signaling molecules with minimal risk of side effects remains an open question. Herein, we assessed the safety of gene therapy using original adeno-associated viral constructs carrying the genes of neurotrophic factors BDNF and GDNF in the early postnatal period of development of experimental animals. The intraventricular injection of AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs into newborn mice was found to provide persistent overexpression of target genes in the hippocampus and cerebral cortex in vivo for four weeks after injection. The application of viral constructs has a multidirectional effect on the weight and body length characteristics of mice in the early postnatal period; however, it ensures the animals' resistance to the development of seizure activity under audiogenic stimulation in the late postnatal period and preserves basic behavioral reactions, emotional status, as well as the mnestic and cognitive abilities of mice after simulated stress. Our results demonstrated the safety of using the AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs in vivo, which indicates the expediency of further testing the constructs as therapeutic anticonvulsants.
2021-12-24 | Disruption of synaptic transmission in the Bed Nucleus of the Stria Terminalis reduces seizure-induced death in DBA/1 mice and alters brainstem E/I balance
ABSTRACT Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic and hypoxic ventilatory response. This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of seizure-induced respiratory arrest, potentially through its outputs to brainstem respiratory regions. SUMMARY STATEMENT This study used a viral expression technique to disrupt synaptic output in the bed nucleus of the stria terminalis (BNST) of DBA/1 audiogenic seizure mice. Inactivating the BNST significantly improved survival following seizures and altered brainstem excitation/inhibition balance.
2017-06-01 | Audiogenic seizure activity following HSV-1 GAD65 sense or antisense injection into inferior colliculus of Long–Evans rat
Herpes virus technology involving manipulation of GAD65 was used to study effects on audiogenic seizures (AGS). Audiogenic seizure behaviors were examined following injections of replication-defective herpes simplex virus (HSV-1) vectors incorporating sense or antisense toward GAD65 along with 10% lac-Z into the central nucleus of inferior colliculus (CNIC) of Long–Evans rats. In seizure-sensitive animals developmentally primed by intense sound exposure, injection of GAD65 in the sense orientation increased wild running latencies and reduced incidence of clonus compared with lac-Z only, unoperated, and vehicle seizure groups. In contrast, infection of CNIC with GAD65 antisense virus resulted in 100% incidence of wild running and clonus behaviors in AGS animals. Unprimed animals not operated continued to show uniform absence of seizure activity. Administration of GAD65 antisense virus into CNIC produced novel wild running and clonus behaviors in some unprimed animals. Staining for β-galactosidase in all vector animals revealed no differences in pattern or numbers of immunoreactive cells at injection sites. Qualitatively, typical small and medium multipolar/stellate and medium fusiform neurons appeared in the CNIC of vector animals. These results demonstrate that HSV-1 vector constructs implanted into the CNIC can predictably influence incidence and severity of AGS and suggest that viral vectors can be useful in studying GABA mechanisms with potential for therapeutic application in epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".
other
2026-02-09 | AUDIOGENIC SEIZURE FITS AND POSTICTAL CATALEPSY IN RATS OF KRUSHINSKY–MOLODKINA STRAIN
The main peculiarities are described of rodent audiogenic epilepsy (seizure fits in response to loud sound), which is the complicated trait connected to brain neurochemistry, displaying peculiarities in a range of brain metabolites as well as to the deviations of muscle tone regulation. Selected for audiogenic epilepsy rat strain Krushinsky–Molodkina is the valuable genetic model of human seizure states. The pattern of neurochemical deviations in this strain is similar to those in other rodent strains with audiogenic epilepsy, which permit to suggest the non-random nature of these phenomena. The post-ictal catalepsy and cataleptic states of other groups are discussed in connection with audiogenic seizure fits. Brain anomalies in these animals emerge, presumably, during early ontogeny.
2025-09-01 | Audiogenic Seizures and Postictal Catalepsy in Rats of Krushinsky–Molodkina Strain
The review summarizes the main peculiarities of rodent audiogenic epilepsy (seizures in response to loud sound), which is related to brain neurochemistry and morphology as well as to the disturbances of muscle tone regulation. The Krushinsky–Molodkina rat strain selectively bred for audiogenic epilepsy is the valuable genetic model of human seizure states. The pattern of neurochemical disturbances in this strain is similar to those in other rodent strains with audiogenic epilepsy, which permit to suggest the non-random nature of these phenomena. The postictal catalepsy and cataleptic states of other types are discussed in relation with audiogenic seizure fits. Brain anomalies in these animals emerge, presumably, during early ontogeny.
2025-03-13 | Changes in the Proteomic Profile After Audiogenic Kindling in the Inferior Colliculus of the GASH/Sal Model of Epilepsy.
Epilepsy is a multifaceted neurological disorder characterized by recurrent seizures and associated with molecular and immune alterations in key brain regions. The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca), a genetic model for audiogenic epilepsy, provides a powerful tool to study seizure mechanisms and resistance in predisposed individuals. This study investigates the proteomic and immune responses triggered by audiogenic kindling in the inferior colliculus, comparing non-responder animals exhibiting reduced seizure severity following repeated stimulation versus GASH/Sal naïve hamsters. To assess auditory pathway functionality, Auditory Brainstem Responses (ABRs) were recorded, revealing reduced neuronal activity in the auditory nerve of non-responders, while central auditory processing remained unaffected. Cytokine profiling demonstrated increased levels of proinflammatory markers, including IL-1 alpha (Interleukin-1 alpha), IL-10 (Interleukin-10), and TGF-beta (Transforming Growth Factor beta), alongside decreased IGF-1 (Insulin-like Growth Factor 1) levels, highlighting systemic inflammation and its interplay with neuroprotection. Building on these findings, a proteomic analysis identified 159 differentially expressed proteins (DEPs). Additionally, bioinformatic approaches, including Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), revealed disrupted pathways related to metabolic and inflammatory epileptic processes and a module potentially linked to a rise in the threshold of seizures, respectively. Differentially expressed genes, identified through bioinformatic and statistical analyses, were validated by RT-qPCR. This confirmed the upregulation of six genes (Gpc1-Glypican-1; Sdc3-Syndecan-3; Vgf-Nerve Growth Factor Inducible; Cpne5-Copine 5; Agap2-Arf-GAP with GTPase domain, ANK repeat, and PH domain-containing protein 2; and Dpp8-Dipeptidyl Peptidase 8) and the downregulation of two (Ralb-RAS-like proto-oncogene B-and S100b-S100 calcium-binding protein B), aligning with reduced seizure severity. This study may uncover key proteomic and immune mechanisms underlying seizure susceptibility, providing possible novel therapeutic targets for refractory epilepsy.
2023-08-31 | The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis
Abstract Epilepsy is a neurological disorder that impacts millions of people worldwide, and it is characterized by the occurrence of recurrent seizures. The pathogenesis of epilepsy is complex, involving dysregulation of various genes and signaling pathways. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a vital role in the regulation of gene expression. They have been found to be involved in the pathogenesis of epilepsy, acting as key regulators of neuronal excitability and synaptic plasticity. In recent years, there has been a growing interest in exploring the miRNA regulatory network in epilepsy. This review summarizes the current knowledge of the regulatory miRNAs involved in inflammation and apoptosis in epilepsy and discusses its potential as a new avenue for developing targeted therapies for the treatment of epilepsy.
2021-06-09 | Putative Causal Variant on Vlgr1 for the Epileptic Phenotype in the Model Wistar Audiogenic Rat
Wistar Audiogenic Rat is an epilepsy model whose animals are predisposed to develop seizures induced by acoustic stimulation. This model was developed by selective reproduction and presents a consistent genetic profile due to the several generations of inbreeding. In this study, we performed an analysis of WAR RNA-Seq data, aiming identified at genetic variants that may be involved in the epileptic phenotype. Seventeen thousand eighty-five predicted variants were identified as unique to the WAR model, of which 15,915 variants are SNPs and 1,170 INDELs. We filter the predicted variants by pre-established criteria and selected five for validation by Sanger sequencing. The genetic variant c.14198T>C in the Vlgr1 gene was confirmed in the WAR model. Vlgr1 encodes an adhesion receptor that is involved in the myelination process, in the development of stereocilia of the inner ear, and was already associated with the audiogenic seizures presented by the mice Frings. The transcriptional quantification of Vlgr1 revealed the downregulation this gene in the corpus quadrigeminum of WAR, and the protein modeling predicted that the mutated residue alters the structure of a domain of the VLGR1 receptor. We believe that Vlgr1 gene may be related to the predisposition of WAR to seizures and suggest the mutation Vlgr1 /Q4695R as putative causal variant, and the first molecular marker of the WAR strain.
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