![]() In all, the combination of targeted therapy along with patient education and support can improve quality of life.ĭysfunctional connectivity and preexisting structural abnormalities of central autonomic network (CAN) regions have been shown on magnetic resonance imaging (MRI) in sudden unexpected death in epilepsy (SUDEP) and may be mechanistically relevant. Clinicians can affect patient quality of life and clinical outcomes through improved seizure cluster education and treatment, such as the development and implementation of a personalized seizure action plan as well as prescriptions for suitable rescue medications indicated for seizure clusters and instructions for their proper use. For patients with seizure clusters, the sense of unpredictability can lead to continuous traumatic stress, during which patients and families live with a heightened level of anxiety. This lack of consensus to define seizure clusters in addition to a lack of education for appropriate treatment can affect quality of life for patients and place a greater burden on patient families and caregivers. There are gaps in understanding between clinicians, their patients, and caregivers regarding acute treatment for seizure clusters, such as the use of rescue medications and emergency services. This can lead to delays in diagnosis and timely treatment. At the clinical level, there is variability in seizure cluster definitions, such as the number and/or type of seizures associated with a cluster as well as the interictal duration between seizures. Benzodiazepines are well‐established treatments for seizure clusters however, there remain barriers to appropriate care. A reduction in neuroinhibition and potentiation of excitatory neurotransmission in CA1 pyramidal neurons represent pathological mechanisms that underlie seizure clusters. Functional changes to GABAA receptors, which play a vital neuroinhibitory role, can include altered GABAA receptor subunit trafficking and cellular localization, intracellular chloride accumulation, and dysregulation of proteins critical to chloride homeostasis. Seizure clusters can break down γ‐aminobutyric acidergic (GABAergic) inhibition of dentate granule cells, leading to hyperactivation. Seizure clusters (also referred to as acute repetitive seizures) consist of several seizures interspersed with brief interictal periods. These results strengthen the evidence for the serotonin hypothesis of SUDEP risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying SUDEP risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Analysis of human SUDEP and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in SUDEP cases. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. ![]() We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioral seizures culminating in late onset sudden mortality predominantly in male mice. Here we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Most monogenic models of SUDEP invoke a failure of inhibitory synaptic drive as a critical pathogenic step. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of SUDEP. ![]() Serotonin (5-HT) signaling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. ![]() Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of epilepsy-related mortality, and the analysis of mouse SUDEP models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. ![]()
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