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Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and\/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure\u2013function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological\/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E\/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E\/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E\/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E\/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.<\/jats:p>","DOI":"10.1093\/hmg\/ddac087","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T19:38:16Z","timestamp":1649878696000},"page":"2964-2988","source":"Crossref","is-referenced-by-count":36,"title":["Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in\n                    <i>Scn2a<\/i>\n                    <i>K1422E<\/i>\n                    mice"],"prefix":"10.1093","volume":"31","author":[{"given":"Dennis M","family":"Echevarria-Cooper","sequence":"first","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"},{"name":"Northwestern University Interdepartmental Neuroscience Program , Northwestern University, Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole A","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita N","family":"Misra","sequence":"additional","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"},{"name":"Department of Pediatrics , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"},{"name":"Ann & Robert H. Lurie Children\u2019s Hospital of Chicago , Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra M","family":"Huffman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Thaxton","sequence":"additional","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher H","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Ben-Shalom","sequence":"additional","affiliation":[{"name":"Mind Institute and Department of Neurology , University of California, Davis, Sacramento, CA 95817 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Neurology , Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M","family":"Lipkin","sequence":"additional","affiliation":[{"name":"Department of Neurology , Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158 , USA"},{"name":"Neuroscience Graduate Program , University of California, San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred L","family":"George Jr","sequence":"additional","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"},{"name":"Northwestern University Interdepartmental Neuroscience Program , Northwestern University, Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J","family":"Bender","sequence":"additional","affiliation":[{"name":"Department of Neurology , Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1726-4769","authenticated-orcid":false,"given":"Jennifer A","family":"Kearney","sequence":"additional","affiliation":[{"name":"Department of Pharmacology , Northwestern University Feinberg School of Medicine, Chicago, IL 60611 , USA"},{"name":"Northwestern University Interdepartmental Neuroscience Program , Northwestern University, Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,13]]},"reference":[{"key":"2022090105181983800_ref1","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.tins.2018.03.011","article-title":"Progress in understanding and treating SCN2A-mediated disorders","volume":"41","author":"Sanders","year":"2018","journal-title":"Trends Neurosci."},{"key":"2022090105181983800_ref2","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1212\/WNL.0b013e3181b9cebc","article-title":"De novo mutations of voltage-gated sodium channel \u03b1II gene SCN2A in intractable epilepsies","volume":"73","author":"Ogiwara","year":"2009","journal-title":"Neurology"},{"key":"2022090105181983800_ref3","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1093\/brain\/awx054","article-title":"Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders","volume":"140","author":"Wolff","year":"2017","journal-title":"Brain"},{"key":"2022090105181983800_ref4","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1111\/epi.14935","article-title":"Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond","volume":"60","author":"Wolff","year":"2019","journal-title":"Epilepsia"},{"key":"2022090105181983800_ref5","doi-asserted-by":"crossref","first-page":"e201912442","DOI":"10.1085\/jgp.201912442","article-title":"Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants","volume":"152","author":"Thompson","year":"2020","journal-title":"J. Gen. Physiol."},{"key":"2022090105181983800_ref6","doi-asserted-by":"crossref","first-page":"10100","DOI":"10.1523\/JNEUROSCI.2476-06.2006","article-title":"Effects in neocortical neurons of mutations of the Nav1.2 Na+ channel causing benign familial neonatal-infantile seizures","volume":"26","author":"Scalmani","year":"2006","journal-title":"J. Neurosci."},{"key":"2022090105181983800_ref7","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.biopsych.2017.01.009","article-title":"Opposing effects on Na V 1.2 function underlie differences between SCN2A variants observed in individuals with autism spectrum disorder or infantile seizures","volume":"82","author":"Ben-Shalom","year":"2017","journal-title":"Biol. 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Sci."},{"key":"2022090105181983800_ref11","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/356441a0","article-title":"Calcium channel characteristics conferred on the sodium channel by single mutations","volume":"356","author":"Heinemann","year":"1992","journal-title":"Nature"},{"key":"2022090105181983800_ref12","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1016\/S0006-3495(96)79505-X","article-title":"On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel","volume":"71","author":"Favre","year":"1996","journal-title":"Biophys. J."},{"key":"2022090105181983800_ref13","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s002490050020","article-title":"Pore properties of rat brain II sodium channels mutated in the selectivity filter domain","volume":"25","author":"Schlief","year":"1996","journal-title":"Eur. Biophys. J. EBJ"},{"key":"2022090105181983800_ref14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0014-5793(91)81159-6","article-title":"Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II","volume":"293","author":"Terlau","year":"1991","journal-title":"FEBS Lett."},{"key":"2022090105181983800_ref15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3390\/md8020219","article-title":"The tetrodotoxin binding site is within the outer vestibule of the sodium channel","volume":"8","author":"Fozzard","year":"2010","journal-title":"Mar. Drugs"},{"key":"2022090105181983800_ref16","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1002\/acn3.51105","article-title":"Functional and pharmacological evaluation of a novel SCN2A variant linked to early-onset epilepsy","volume":"7","author":"Adney","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"2022090105181983800_ref17","doi-asserted-by":"crossref","first-page":"820","DOI":"10.15252\/embj.201593285","article-title":"Molecular basis of ion permeability in a voltage-gated sodium channel","volume":"35","author":"Naylor","year":"2016","journal-title":"EMBO J."},{"key":"2022090105181983800_ref18","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1016\/j.biocel.2009.01.016","article-title":"Protein\u2013protein interactions involving voltage-gated sodium channels: post-translational regulation, intracellular trafficking and functional expression","volume":"41","author":"Shao","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2022090105181983800_ref19","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1016\/S0006-3495(00)76829-9","article-title":"Neuronal death and perinatal lethality in voltage-gated sodium channel alpha(II)-deficient mice","volume":"78","author":"Planells-Cases","year":"2000","journal-title":"Biophys. J."},{"key":"2022090105181983800_ref20","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/nn.2359","article-title":"Distinct contributions of Na v 1.6 and Na v 1.2 in action potential initiation and backpropagation","volume":"12","author":"Hu","year":"2009","journal-title":"Nat. Neurosci."},{"key":"2022090105181983800_ref21","doi-asserted-by":"crossref","first-page":"437","DOI":"10.4161\/chan.3.6.10201","article-title":"AKV2.1 gating modifier binding assay suitable for high throughput screening","volume":"3","author":"Schmalhofer","year":"2009","journal-title":"Channels"},{"key":"2022090105181983800_ref22","doi-asserted-by":"crossref","first-page":"109483","DOI":"10.1016\/j.celrep.2021.109483","article-title":"Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells","volume":"36","author":"Spratt","year":"2021","journal-title":"Cell Rep."},{"key":"2022090105181983800_ref23","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S0896-6273(00)00164-1","article-title":"Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons","volume":"28","author":"Geiger","year":"2000","journal-title":"Neuron"},{"key":"2022090105181983800_ref24","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.neuron.2014.08.036","article-title":"Ultrafast action potentials mediate kilohertz signaling at a central synapse","volume":"84","author":"Ritzau-Jost","year":"2014","journal-title":"Neuron"},{"key":"2022090105181983800_ref25","doi-asserted-by":"crossref","first-page":"6611","DOI":"10.1523\/JNEUROSCI.4208-13.2014","article-title":"Distinct Kv channel subtypes contribute to differences in spike signaling properties in the axon initial segment and presynaptic boutons of cerebellar interneurons","volume":"34","author":"Rowan","year":"2014","journal-title":"J. Neurosci."},{"key":"2022090105181983800_ref26","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1113\/JP280554","article-title":"Optical measurement of physiological sodium currents in the axon initial segment","volume":"599","author":"Filipis","year":"2021","journal-title":"J. Physiol."},{"key":"2022090105181983800_ref27","doi-asserted-by":"crossref","first-page":"3764","DOI":"10.1523\/JNEUROSCI.2843-20.2021","article-title":"Functional microstructure of CaV-mediated calcium signaling in the axon initial segment","volume":"41","author":"Lipkin","year":"2021","journal-title":"J. Neurosci."},{"key":"2022090105181983800_ref28","doi-asserted-by":"crossref","first-page":"e54566","DOI":"10.7554\/eLife.54566","article-title":"Ca2+ entry through NaV channels generates submillisecond axonal Ca2+ signaling","volume":"9","author":"Hanemaaijer","year":"2020","journal-title":"elife"},{"key":"2022090105181983800_ref29","doi-asserted-by":"crossref","DOI":"10.1016\/j.pediatrneurol.2013.03.002","article-title":"SCN2A mutation is associated with infantile spasms and bitemporal glucose hypometabolism","volume":"49","author":"Sundaram","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"2022090105181983800_ref30","doi-asserted-by":"crossref","DOI":"10.21769\/BioProtoc.2309","article-title":"The repeated flurothyl seizure model in mice","volume":"7","author":"Ferland","year":"2017","journal-title":"Bio-Protoc."},{"key":"2022090105181983800_ref31","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nrn2851","article-title":"Behavioural phenotyping assays for mouse models of autism","volume":"11","author":"Silverman","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"2022090105181983800_ref32","doi-asserted-by":"crossref","first-page":"12886","DOI":"10.1038\/s41598-019-49392-7","article-title":"NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age","volume":"9","author":"L\u00e9na","year":"2019","journal-title":"Sci. Rep."},{"key":"2022090105181983800_ref33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13229-019-0265-5","article-title":"Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity","volume":"10","author":"Tatsukawa","year":"2019","journal-title":"Mol. Autism"},{"key":"2022090105181983800_ref34","doi-asserted-by":"crossref","DOI":"10.1176\/appi.books.9780890425596","volume-title":"Diagnostic and Statistical Manual of Mental Disorders","author":"American Psychiatric Association","year":"2013","edition":"5th"},{"key":"2022090105181983800_ref35","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nn.4276","article-title":"Neurobiology of social behavior abnormalities in autism and Williams syndrome","volume":"19","author":"Barak","year":"2016","journal-title":"Nat. Neurosci."},{"key":"2022090105181983800_ref36","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.braindev.2011.09.016","article-title":"Clinical spectrum of SCN2A mutations","volume":"34","author":"Shi","year":"2012","journal-title":"Brain Dev."},{"key":"2022090105181983800_ref37","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1136\/jmedgenet-2014-102608","article-title":"Genotype phenotype associations across the voltage-gated sodium channel family","volume":"51","author":"Brunklaus","year":"2014","journal-title":"J. Med. Genet."},{"key":"2022090105181983800_ref38","doi-asserted-by":"crossref","DOI":"10.1186\/s10020-019-0073-6","article-title":"Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes","volume":"25","author":"Begemann","year":"2019","journal-title":"Mol. Med."},{"key":"2022090105181983800_ref39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41436-021-01120-1","article-title":"Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A -related disorders","volume":"23","author":"Crawford","year":"2021","journal-title":"Genet. Med."},{"key":"2022090105181983800_ref40","article-title":"Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors. JCI","volume":"6","author":"Wang","year":"2021","journal-title":"Insight"},{"key":"2022090105181983800_ref41","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1021\/ar5002878","article-title":"Ion selectivity strategies of sodium channel selectivity filters","volume":"47","author":"Dudev","year":"2014","journal-title":"Acc. Chem. Res."},{"key":"2022090105181983800_ref42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0896-6273(04)00148-5","article-title":"A voltage-gated calcium-selective channel encoded by a sodium channel-like gene","volume":"42","author":"Zhou","year":"2004","journal-title":"Neuron"},{"key":"2022090105181983800_ref43","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2015.00153","article-title":"Selectivity filters and cysteine-rich extracellular loops in voltage-gated sodium, calcium, and NALCN channels","volume":"6","author":"Stephens","year":"2015","journal-title":"Front. Physiol."},{"key":"2022090105181983800_ref44","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.celrep.2012.06.016","article-title":"Convergent evolution of sodium Ion selectivity in metazoan neuronal signaling","volume":"2","author":"Gur Barzilai","year":"2012","journal-title":"Cell Rep."},{"key":"2022090105181983800_ref45","doi-asserted-by":"crossref","first-page":"10619","DOI":"10.1073\/pnas.1201884109","article-title":"Adaptive evolution of voltage-gated sodium channels: the first 800 million years","volume":"109","author":"Zakon","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022090105181983800_ref46","doi-asserted-by":"crossref","first-page":"109495","DOI":"10.1016\/j.celrep.2021.109495","article-title":"Severe deficiency of the voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice","volume":"36","author":"Zhang","year":"2021","journal-title":"Cell Rep."},{"key":"2022090105181983800_ref47","doi-asserted-by":"crossref","first-page":"7991","DOI":"10.1523\/JNEUROSCI.22-18-07991.2002","article-title":"Calmodulin is an auxiliary subunit of KCNQ2\/3 potassium channels","volume":"22","author":"Wen","year":"2002","journal-title":"J. Neurosci."},{"key":"2022090105181983800_ref48","doi-asserted-by":"crossref","first-page":"45004","DOI":"10.1074\/jbc.M407286200","article-title":"Calmodulin mediates Ca2+ sensitivity of sodium channels*","volume":"279","author":"Kim","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2022090105181983800_ref49","doi-asserted-by":"crossref","first-page":"15509","DOI":"10.1038\/srep15509","article-title":"Ca(2+)\/calmodulin regulates Kv\u03b21.1-mediated inactivation of voltage-gated K(+) channels","volume":"5","author":"Swain","year":"2015","journal-title":"Sci. Rep."},{"key":"2022090105181983800_ref50","doi-asserted-by":"crossref","first-page":"5846","DOI":"10.1523\/JNEUROSCI.0310-17.2017","article-title":"D3 receptors regulate excitability in a unique class of prefrontal pyramidal cells","volume":"37","author":"Clarkson","year":"2017","journal-title":"J. Neurosci."},{"key":"2022090105181983800_ref51","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/0896-6273(89)90238-9","article-title":"Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons","volume":"3","author":"Westenbroek","year":"1989","journal-title":"Neuron"},{"key":"2022090105181983800_ref52","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/(SICI)1096-9861(19990920)412:2<342::AID-CNE11>3.0.CO;2-2","article-title":"Type I and type II Na+ channel \u03b1-subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain","volume":"412","author":"Gong","year":"1999","journal-title":"J. Comp. Neurol."},{"key":"2022090105181983800_ref53","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1152\/physrev.00002.2008","article-title":"Localization and targeting of voltage-dependent ion channels in mammalian central neurons","volume":"88","author":"Vacher","year":"2008","journal-title":"Physiol. Rev."},{"key":"2022090105181983800_ref54","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1126\/science.1187958","article-title":"Molecular identity of dendritic voltage-gated sodium channels","volume":"328","author":"Lorincz","year":"2010","journal-title":"Science"},{"key":"2022090105181983800_ref55","doi-asserted-by":"crossref","first-page":"6112","DOI":"10.1523\/JNEUROSCI.0119-20.2020","article-title":"Activity and cytosolic Na+ regulate synaptic vesicle endocytosis","volume":"40","author":"Zhu","year":"2020","journal-title":"J. Neurosci."},{"key":"2022090105181983800_ref56","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.tins.2016.01.005","article-title":"The nanophysiology of fast transmitter release","volume":"39","author":"Stanley","year":"2016","journal-title":"Trends Neurosci."},{"key":"2022090105181983800_ref57","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3389\/fncel.2019.00221","article-title":"Modulation of ion channels in the axon: mechanisms and function","volume":"13","author":"Burke","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"2022090105181983800_ref58","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1113\/jphysiol.1973.sp010386","article-title":"Calcium inward currents in internally perfused giant axons","volume":"235","author":"Meves","year":"1973","journal-title":"J. Physiol."},{"key":"2022090105181983800_ref59","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2021.100783","article-title":"Heterologous functional expression of ascidian Nav1 channels and close relationship with the evolutionary ancestor of vertebrate Nav channels","volume":"296","author":"Kawai","year":"2021","journal-title":"J. Biol. Chem."},{"key":"2022090105181983800_ref60","article-title":"Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice","volume":"1","year":"2018","journal-title":"Commun. Biol."},{"key":"2022090105181983800_ref61","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1093\/hmg\/ddx104","article-title":"Scn2a deletion improves survival and brain\u2013heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP)","volume":"26","author":"Mishra","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"2022090105181983800_ref62","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s00335-005-0049-4","article-title":"Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a","volume":"16","author":"Bergren","year":"2005","journal-title":"Mamm. Genome Off. J. Int. Mamm. Genome Soc."},{"key":"2022090105181983800_ref63","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1601-183X.2004.00094.x","article-title":"Genetic modifiers of the Kv\u03b22-null phenotype in mice","volume":"4","author":"Connor","year":"2005","journal-title":"Genes Brain Behav."},{"key":"2022090105181983800_ref64","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1093\/hmg\/ddm248","article-title":"The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy","volume":"16","author":"Martin","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2022090105181983800_ref65","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1111\/j.1528-1167.2012.03512.x","article-title":"Quantitative trait locus on distal Chromosome 1 regulates the occurrence of spontaneous Spike Wave Discharges in DBA\/2 mice","volume":"53","author":"Bessaih","year":"2012","journal-title":"Epilepsia"},{"key":"2022090105181983800_ref66","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004454","article-title":"Unraveling Genetic Modifiers in the Gria4 Mouse Model of Absence Epilepsy","volume":"10","author":"Frankel","year":"2014","journal-title":"PLoS Genet."},{"key":"2022090105181983800_ref67","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s00335-014-9509-z","article-title":"Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)?","volume":"25","author":"Kehrl","year":"2014","journal-title":"Mamm. Genome"},{"key":"2022090105181983800_ref68","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/gbb.12099","article-title":"Mapping genetic modifiers of survival in a mouse model of Dravet syndrome","volume":"13","author":"Miller","year":"2014","journal-title":"Genes Brain Behav."},{"key":"2022090105181983800_ref69","doi-asserted-by":"crossref","first-page":"e103","DOI":"10.1111\/epi.13390","article-title":"Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a","volume":"57","author":"Calhoun","year":"2016","journal-title":"Epilepsia"},{"key":"2022090105181983800_ref70","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1212\/WNL.0b013e3181f8812e","article-title":"SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain","volume":"75","author":"Liao","year":"2010","journal-title":"Neurology"},{"key":"2022090105181983800_ref71","first-page":"e89810","article-title":"Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis","volume":"1","author":"Schattling","journal-title":"JCI Insight"},{"key":"2022090105181983800_ref72","volume-title":"Characterization of hippocampal network activity and pharmacological pilot study in a Scn2a epilapsy mouse model","author":"Schob","year":"2018"},{"key":"2022090105181983800_ref73","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1093\/brain\/awaa147","article-title":"Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice","volume":"143","author":"Amador","year":"2020","journal-title":"Brain"},{"key":"2022090105181983800_ref74","doi-asserted-by":"crossref","first-page":"104758","DOI":"10.1016\/j.nbd.2020.104758","article-title":"Altered excitatory transmission onto hippocampal interneurons in the IQSEC2 mouse model of X-linked neurodevelopmental disease","volume":"137","author":"Sah","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"2022090105181983800_ref75","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1093\/hmg\/ddp081","article-title":"Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice","volume":"18","author":"Papale","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2022090105181983800_ref76","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0896-6273(01)00265-3","article-title":"Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon","volume":"30","author":"Boiko","year":"2001","journal-title":"Neuron"},{"key":"2022090105181983800_ref77","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0896-6273(01)00266-5","article-title":"Differential control of clustering of the sodium channels Nav1.2 and Nav1.6 at developing CNS nodes of ranvier","volume":"30","author":"Kaplan","year":"2001","journal-title":"Neuron"},{"key":"2022090105181983800_ref78","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1113\/jphysiol.2005.097022","article-title":"Differential targeting and functional specialization of sodium channels in cultured cerebellar granule cells","volume":"569","author":"Osorio","year":"2005","journal-title":"J. Physiol."},{"key":"2022090105181983800_ref79","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1111\/j.1528-1157.2000.tb00203.x","article-title":"Estradiol facilitates kainic acid\u2014induced, but not flurothyl-induced, behavioral seizure activity in adult female rats","volume":"41","author":"Woolley","year":"2000","journal-title":"Epilepsia"},{"key":"2022090105181983800_ref80","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.expneurol.2005.07.007","article-title":"Seizure susceptibility in intact and ovariectomized female rats treated with the convulsant pilocarpine","volume":"196","author":"Scharfman","year":"2005","journal-title":"Exp. Neurol."},{"key":"2022090105181983800_ref81","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.neuroscience.2010.07.037","article-title":"Neurosteroid withdrawal regulates GABA-A receptor \u03b14-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway","volume":"170","author":"Gangisetty","year":"2010","journal-title":"Neuroscience"},{"key":"2022090105181983800_ref82","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.nbd.2014.05.027","article-title":"Using sex differences in the developing brain to identify nodes of influence for seizure susceptibility and epileptogenesis","volume":"72","author":"Kight","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"2022090105181983800_ref83","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.brainres.2018.02.031","article-title":"Neurosteroid regulation of GABAA receptors: A role in catamenial epilepsy","volume":"1703","author":"Joshi","year":"2019","journal-title":"Brain Res."},{"key":"2022090105181983800_ref84","doi-asserted-by":"crossref","first-page":"113492","DOI":"10.1016\/j.expneurol.2020.113492","article-title":"Seizure burden fluctuates with the female reproductive cycle in a mouse model of chronic temporal lobe epilepsy","volume":"334","author":"Li","year":"2020","journal-title":"Exp. Neurol."},{"key":"2022090105181983800_ref85","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/nn0909-1075","article-title":"Troublesome variability in mouse studies","volume":"12","year":"2009","journal-title":"Nat. Neurosci."},{"key":"2022090105181983800_ref86","doi-asserted-by":"crossref","first-page":"522","DOI":"10.3390\/brainsci11040522","article-title":"Behavior testing in rodents: highlighting potential confounds affecting variability and reproducibility","volume":"11","author":"Sar\u00e9","year":"2021","journal-title":"Brain Sci."},{"key":"2022090105181983800_ref87","doi-asserted-by":"crossref","first-page":"e12725","DOI":"10.1111\/gbb.12725","article-title":"Generation and basic characterization of a gene-trap knockout mouse model of Scn2a with a substantial reduction of voltage-gated sodium channel Nav1.2 expression","volume":"20","author":"Eaton","year":"2021","journal-title":"Genes Brain Behav."},{"key":"2022090105181983800_ref88","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3389\/fnmol.2019.00145","article-title":"Scn2a haploinsufficiency in mice suppresses hippocampal neuronal excitability, excitatory synaptic drive, and long-term potentiation, and spatial learning and memory","volume":"12","author":"Shin","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"2022090105181983800_ref89","doi-asserted-by":"crossref","DOI":"10.1002\/brb3.2041","article-title":"Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic-like behaviors due to Scn2a haploinsufficiency","volume":"11","author":"Indumathy","year":"2021","journal-title":"Brain Behav."},{"key":"2022090105181983800_ref90","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nature09582","article-title":"GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes","volume":"468","author":"Chao","year":"2010","journal-title":"Nature"},{"key":"2022090105181983800_ref91","doi-asserted-by":"crossref","first-page":"4920","DOI":"10.1073\/pnas.1102233108","article-title":"Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism","volume":"108","author":"Mejias","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022090105181983800_ref92","doi-asserted-by":"crossref","first-page":"10194","DOI":"10.1523\/JNEUROSCI.0564-21.2021","article-title":"Hyperexcitability and pharmacological responsiveness of cortical neurons derived from human iPSCs carrying epilepsy-associated sodium channel Nav1.2-L1342P genetic variant","volume":"41","author":"Que","year":"2021","journal-title":"J. Neurosci"},{"key":"2022090105181983800_ref93","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1159\/000447526","article-title":"Phenotypic variability from benign infantile epilepsy to ohtahara syndrome associated with a novel mutation in SCN2A","volume":"7","author":"Syrbe","year":"2016","journal-title":"Mol. Syndromol."},{"key":"2022090105181983800_ref94","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.mcn.2007.03.003","article-title":"A childhood epilepsy mutation reveals a role for developmentally regulated splicing of a sodium channel","volume":"35","author":"Xu","year":"2007","journal-title":"Mol. Cell. Neurosci."},{"key":"2022090105181983800_ref95","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.neuroscience.2009.12.011","article-title":"Differential expression of exon 5 splice variants of sodium channel \u03b1 subunit mRNAs in the developing mouse brain","volume":"166","author":"Gazina","year":"2010","journal-title":"Neuroscience"},{"key":"2022090105181983800_ref96","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1093\/hmg\/ddu562","article-title":"\u2018Neonatal\u2019 Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour","volume":"24","author":"Gazina","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2022090105181983800_ref97","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0306-4522(00)00479-6","article-title":"A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities","volume":"102","author":"Kearney","year":"2001","journal-title":"Neuroscience"},{"key":"2022090105181983800_ref98","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.nbd.2010.11.016","article-title":"Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus","volume":"41","author":"Hawkins","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"2022090105181983800_ref99","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1073\/pnas.1615774114","article-title":"CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice","volume":"114","author":"Thompson","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022090105181983800_ref100","article-title":"Cryptic prokaryotic promoters explain instability of recombinant neuronal sodium channels in bacteria","volume":"296","year":"2021","journal-title":"J. Biol. Chem."},{"key":"2022090105181983800_ref101","article-title":"SCN1A splice variants exhibit divergent sensitivity to commonly used antiepileptic drugs","volume":"52","year":"2011","journal-title":"Epilepsia"},{"key":"2022090105181983800_ref102","article-title":"Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression","volume":"287","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2022090105181983800_ref103","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","year":"2020","journal-title":"PLOS Biol."},{"key":"2022090105181983800_ref104","doi-asserted-by":"crossref","first-page":"7740","DOI":"10.1523\/JNEUROSCI.6136-09.2010","article-title":"Isolation of somatic Na+ currents by selective inactivation of axonal channels with a voltage prepulse","volume":"30","author":"Milescu","year":"2010","journal-title":"J. Neurosci."},{"key":"2022090105181983800_ref105","article-title":"Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in dravet syndrome mice","volume":"65","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"2022090105181983800_ref106","article-title":"Fine mapping of a dravet syndrome modifier locus on mouse chromosome 5 and candidate gene analysis by RNA-seq","volume":"12","year":"2016","journal-title":"PLoS Genet."},{"key":"2022090105181983800_ref107","article-title":"Behavioural and pharmacological characterisation of the elevated ``zero-maze'' as an animal model of anxiety","volume":"116","year":"1994","journal-title":"Psychopharmacology (Berl.)"},{"key":"2022090105181983800_ref108","article-title":"Simple behavioral assessment of mouse olfaction","volume":"48","year":"2010","journal-title":"Curr. Protoc. 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