{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T02:57:04Z","timestamp":1785466624556,"version":"3.56.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T00:00:00Z","timestamp":1662508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"<jats:p>Sudden unexpected death in epilepsy (SUDEP) accounts for the deaths of 8\u201317% of patients with epilepsy. Although the mechanisms of SUDEP are essentially unknown, one proposed mechanism is respiratory arrest initiated by a convulsive seizure. In mice, we have previously observed that extended apnea occurs during the tonic phase of seizures. Although often survived, tonic seizures became fatal when breathing did not immediately recover postictally. We also found that respiratory muscles were tonically contracted during the apnea, suggesting that muscle contraction could be the cause of apnea. In the present study, we tested the hypothesis that pyramidal neurons of the motor cortex drive motor units during the tonic phase, which produces apnea. Mice harboring the patient-derived N1768D point mutation of an <jats:italic>Scn8a<\/jats:italic> allele were crossed with transgenic mice such that inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) receptors were selectively expressed in excitatory forebrain neurons. We then triggered audiogenic and hippocampal (HC) stimulated seizures under control conditions and when excitatory forebrain neurons were inhibited with the synthetic ligand Clozapine-<jats:italic>N<\/jats:italic>-Oxide (CNO). We found that inhibition with CNO was sufficient to increase seizure threshold of HC stimulated, but not audiogenic, seizures. In addition, regardless of seizure type, CNO nearly eliminated epileptiform activity that occurred proximal to the tonic phase; however, the seizure behaviors, notably the tonic phase and concomitant apnea, were unchanged. We interpret these results to indicate that while cortical neurons are likely critical for epileptogenesis and seizure initiation, the behavioral manifestations of tonic seizures are generated by neural circuitry in the mid- and\/or hindbrain.<\/jats:p>","DOI":"10.3389\/fncir.2022.1002013","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T09:51:22Z","timestamp":1662544282000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Forebrain epileptiform activity is not required for seizure-induced apnea in a mouse model of Scn8a epilepsy"],"prefix":"10.3389","volume":"16","author":[{"given":"Ian C.","family":"Wenker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis R.","family":"Boscia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anas","family":"Tariq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Miralles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica C.","family":"Hanflink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Saraf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj K.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1177\/0883073809348355","article-title":"Increased risk of death among children with lennox-gastaut syndrome and infantile spasms.","volume":"25","author":"Autry","year":"2009","journal-title":"J. Child Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3239","DOI":"10.1093\/brain\/awn277","article-title":"Ictal hypoxemia in localization-related epilepsy: Analysis of incidence, severity and risk factors.","volume":"131","author":"Bateman","year":"2008","journal-title":"Brain"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S52","DOI":"10.1111\/j.1528-1167.1997.tb06295.x","article-title":"Sudden unexplained death in epilepsy: An intracranially monitored case.","volume":"38","author":"Bird","year":"1997","journal-title":"Epilepsia"},{"key":"B4","doi-asserted-by":"publisher","first-page":"4395","DOI":"10.1113\/jphysiol.2014.277574","article-title":"Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality.","volume":"592","author":"Buchanan","year":"2014","journal-title":"J. Physiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1093\/brain\/awy324","article-title":"Prominent role of forebrain excitatory neurons in SCN8A encephalopathy.","volume":"142","author":"Bunton-Stasyshyn","year":"2019","journal-title":"Brain"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.17226\/12910","author":"Council","year":"2011","journal-title":"Guide for the care and use of laboratory animals"},{"key":"B7","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1001\/archneur.1986.00520020080028","article-title":"Sudden unexpected death of epileptic patient due to cardiac arrhythmia after seizure.","volume":"43","author":"Dasheiff","year":"1986","journal-title":"Arch. Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1056\/NEJMra1010481","article-title":"Sudden, unexpected death in epilepsy.","volume":"365","author":"Devinsky","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"10281","DOI":"10.1523\/JNEUROSCI.0888-15.2015","article-title":"Breathing inhibited when seizures spread to the amygdala and upon amygdala stimulation.","volume":"35","author":"Dlouhy","year":"2015","journal-title":"J. Neurosci."},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.1093\/med\/9780199746545.003.0020","article-title":"Brainstem networks","author":"Faingold","year":"2012","journal-title":"Jasper\u2019s basic mechanisms of the epilepsies"},{"key":"B11","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/0006-8993(95)01116-1","article-title":"Pontine reticular formation neurons exhibit a premature and precipitous increase in acoustic responses prior to audiogenic seizures in genetically epilepsy-prone rats.","volume":"704","author":"Faingold","year":"1995","journal-title":"Brain Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/B978-0-12-804066-9.00032-8","article-title":"Genetic models of reflex epilepsy and SUDEP in rats and mice","author":"Faingold","year":"2017","journal-title":"Models of seizures and epilepsy"},{"key":"B13","doi-asserted-by":"publisher","first-page":"S77","DOI":"10.1111\/epi.16319","article-title":"Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes.","volume":"60","author":"Gardella","year":"2019","journal-title":"Epilepsia"},{"key":"B14","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/j.1528-1157.1963.tb05206.x","article-title":"An electro-clinical study of generalized epileptic seizures of tonic expression.","volume":"4","author":"Gastaut","year":"1963","journal-title":"Epilepsia"},{"key":"B15","doi-asserted-by":"publisher","first-page":"6309","DOI":"10.1523\/JNEUROSCI.22-15-06309.2002","article-title":"Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage.","volume":"22","author":"Gorski","year":"2002","journal-title":"J. Neurosci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1159\/000517686","article-title":"Antisense oligonucleotide therapy for neurodevelopmental disorders.","volume":"43","author":"Hill","year":"2021","journal-title":"Dev. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/35021059","article-title":"Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex.","volume":"406","author":"Iwasato","year":"2000","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"9633","DOI":"10.1523\/JNEUROSCI.1713-19.2019","article-title":"Apnea associated with brainstem seizures in Cacna1aS218L mice is caused by medullary spreading depolarization.","volume":"39","author":"Jansen","year":"2019","journal-title":"J. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1172\/JCI94999","article-title":"Severe peri-ictal respiratory dysfunction is common in Dravet syndrome.","volume":"128","author":"Kim","year":"2018","journal-title":"J. Clin. Invest."},{"key":"B20","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1001\/jamaneurol.2017.3344","article-title":"Cortical structures associated with human blood pressure control.","volume":"75","author":"Lacuey","year":"","journal-title":"JAMA Neurol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1111\/epi.14006","article-title":"The incidence and significance of periictal apnea in epileptic seizures.","volume":"59","author":"Lacuey","year":"","journal-title":"Epilepsia"},{"key":"B22","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1212\/WNL.0000000000001211","article-title":"The phenotypic spectrum of SCN8A encephalopathy.","volume":"84","author":"Larsen","year":"2015","journal-title":"Neurology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1002\/ana.25676","article-title":"Scn8a antisense oligonucleotide is protective in mouse models of SCN8A encephalopathy and Dravet syndrome.","volume":"87","author":"Lenk","year":"2020","journal-title":"Ann. Neurol."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/acprof:oso\/9780195306637.001.0001","author":"Llewellyn-Smith","year":"2011","journal-title":"Central regulation of autonomic functions"},{"key":"B25","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1093\/brain\/awy325","article-title":"Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice.","volume":"142","author":"Loonen","year":"2019","journal-title":"Brain"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3078","article-title":"A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing.","volume":"15","author":"Madisen","year":"2012","journal-title":"Nat. Neurosci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain.","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1111\/epi.16432","article-title":"Audiogenic seizure as a model of sudden death in epilepsy: A comparative study between four inbred mouse strains from early life to adulthood.","volume":"61","author":"Martin","year":"2020","journal-title":"Epilepsia"},{"key":"B29","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1111\/j.1528-1167.2011.03358.x","article-title":"Unifying the definitions of sudden unexpected death in epilepsy.","volume":"53","author":"Nashef","year":"2012","journal-title":"Epilepsia"},{"key":"B30","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1136\/jnnp.60.3.297","article-title":"Apnoea and bradycardia during epileptic seizures: Relation to sudden death in epilepsy.","volume":"60","author":"Nashef","year":"1996","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B31","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1016\/S0140-6736(98)05114-9","article-title":"Risk factors for sudden unexpected death in epilepsy: A case control study.","volume":"353","author":"Nilsson","year":"1999","journal-title":"Lancet"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.3171\/2019.1.JNS183157","article-title":"The effect of seizure spread to the amygdala on respiration and onset of ictal central apnea.","volume":"132","author":"Nobis","year":"2019","journal-title":"J. Neurosurg. JNS"},{"key":"B33","doi-asserted-by":"publisher","first-page":"7643","DOI":"10.1523\/JNEUROSCI.2709-16.2017","article-title":"Aberrant sodium channel currents and hyperexcitability of medial entorhinal cortex neurons in a mouse model of SCN8A encephalopathy.","volume":"37","author":"Ottolini","year":"2017","journal-title":"J. Neurosci."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2021.108032","article-title":"Mortality in tuberous sclerosis complex.","volume":"121","author":"Parthasarathy","year":"2021","journal-title":"Epilepsy Behav."},{"key":"B35","first-page":"381","article-title":"Upper motor neuron control of the brainstem and spinal cord","author":"Purves","year":"2018","journal-title":"Neuroscience"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.134852","article-title":"A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy.","volume":"5","author":"Rhone","year":"2020","journal-title":"JCI Insight"},{"key":"B37","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/S1474-4422(13)70214-X","article-title":"Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): A retrospective study.","volume":"12","author":"Ryvlin","year":"2013","journal-title":"Lancet Neurol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1111\/j.1528-1157.2000.tb00128.x","article-title":"Postictal central apnea as a cause of SUDEP: Evidence from near-SUDEP incident.","volume":"41","author":"So","year":"2000","journal-title":"Epilepsia"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08810-4","article-title":"Embryonic hindbrain patterning genes delineate distinct cardio-respiratory and metabolic homeostatic populations in the adult.","volume":"7","author":"Sun","year":"2017","journal-title":"Sci. Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/J.YEBEH.2012.12.018","article-title":"Sudden unexpected death in epilepsy: From the lab to the clinic setting.","volume":"26","author":"Terra","year":"2013","journal-title":"Epilepsy Behav."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1111\/epi.12666","article-title":"Sudden unexpected death in epilepsy: Assessing the public health burden.","volume":"55","author":"Thurman","year":"2014","journal-title":"Epilepsia"},{"key":"B42","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/J.YEBEH.2012.09.017","article-title":"Potential mechanisms of sudden unexpected death in epilepsy.","volume":"26","author":"Tolstykh","year":"2013","journal-title":"Epilepsy Behav."},{"key":"B43","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.yebeh.2019.03.043","article-title":"Generalized tonic seizures with autonomic signs are the hallmark of SCN8A developmental and epileptic encephalopathy.","volume":"96","author":"Trivisano","year":"2019","journal-title":"Epilepsy Behav."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00166","article-title":"Incidence, recurrence, and risk factors for peri-ictal central apnea and sudden unexpected death in epilepsy.","volume":"10","author":"Vilella","year":"2019","journal-title":"Front. Neurol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1093\/hmg\/ddu470","article-title":"Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy.","volume":"24","author":"Wagnon","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"B46","doi-asserted-by":"publisher","first-page":"9257","DOI":"10.1523\/JNEUROSCI.0718-21.2021","article-title":"Somatostatin-positive interneurons contribute to seizures in SCN8A epileptic encephalopathy.","volume":"41","author":"Wengert","year":"","journal-title":"J. Neurosci."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.581048","article-title":"Adrenergic mechanisms of audiogenic seizure-induced death in a mouse model of SCN8A encephalopathy.","volume":"15","author":"Wengert","year":"","journal-title":"Front. Neurosci."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEUROPHARM.2019.107699","article-title":"Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy.","volume":"158","author":"Wengert","year":"2019","journal-title":"Neuropharmacology"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2021.147743","article-title":"Targeted augmentation of nuclear gene output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and reduces seizures in a mouse model of Dravet syndrome.","volume":"1775","author":"Wengert","year":"2022","journal-title":"Brain Res."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.795145","article-title":"Peri-ictal autonomic control of cardiac function and seizure-induced death.","volume":"15","author":"Wenker","year":"2022","journal-title":"Front. Neurosci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1002\/ana.26053","article-title":"Postictal death is associated with tonic phase apnea in a mouse model of sudden unexpected death in epilepsy.","volume":"89","author":"Wenker","year":"2021","journal-title":"Ann. Neurol."},{"key":"B52","article-title":"Treatment of epilepsy during pregnancy","author":"Wyllie","year":"2015","journal-title":"Wyllie\u2019s Treatment of Epilepsy"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2020.106440","article-title":"Autonomic seizure with prominent apnea in patient with SCN8A-related epileptic encephalopathy.","volume":"167","author":"Zawadzka","year":"2020","journal-title":"Epilepsy Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1002\/dvg.22949","article-title":"Cre-dependent DREADD (Designer receptors exclusively activated by designer drugs) mice.","volume":"54","author":"Zhu","year":"2016","journal-title":"Genesis"}],"container-title":["Frontiers in Neural Circuits"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2022.1002013\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T09:51:31Z","timestamp":1662544291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2022.1002013\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,7]]},"references-count":54,"alternative-id":["10.3389\/fncir.2022.1002013"],"URL":"https:\/\/doi.org\/10.3389\/fncir.2022.1002013","relation":{},"ISSN":["1662-5110"],"issn-type":[{"value":"1662-5110","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,7]]},"article-number":"1002013"}}