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Inherited, biallelic, loss\u2010of\u2010function variants in <jats:italic>SCN1B<\/jats:italic>, encoding the \u03b21\/\u03b21B subunits, are linked to early infantile DEE (EIEE52). <jats:italic>De novo<\/jats:italic>, monoallelic variants in <jats:italic>SCN1A<\/jats:italic> (Nav1.1), <jats:italic>SCN2A<\/jats:italic> (Nav1.2), <jats:italic>SCN3A<\/jats:italic> (Nav1.3), and <jats:italic>SCN8A<\/jats:italic> (Nav1.6) are also linked to DEEs. While these VGSC\u2010linked DEEs have similar presentations, they have diverse mechanisms of altered neuronal excitability. Mouse models have suggested that <jats:italic>Scn2a<\/jats:italic>\u2010, <jats:italic>Scn3a<\/jats:italic>\u2010, and <jats:italic>Scn8a<\/jats:italic>\u2010linked DEE variants are, in general, gain of function, resulting in increased persistent or resurgent sodium current (I<jats:sub>Na<\/jats:sub>) and pyramidal neuron hyperexcitability. In contrast, <jats:italic>Scn1a<\/jats:italic>\u2010linked DEE variants, in general, are loss\u2010of\u2010function, resulting in decreased I<jats:sub>Na<\/jats:sub> and hypoexcitability of fast\u2010spiking interneurons. VGSC \u03b21 subunits associate with Nav1.1, Nav1.2, Nav1.3, and Nav1.6 and are expressed throughout the brain, raising the possibility that insults to both pyramidal and interneuron excitability may drive EIEE52 pathophysiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated excitability defects in pyramidal and parvalbumin\u2010positive (PV +) interneurons in the <jats:italic>Scn1b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> model of EIEE52. We also used <jats:italic>Scn1b<jats:sup>FL\/FL<\/jats:sup><\/jats:italic> mice to delete <jats:italic>Scn1b<\/jats:italic> in specific neuronal populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Scn1b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> cortical PV\u00a0+\u00a0interneurons were hypoexcitable, with reduced I<jats:sub>Na<\/jats:sub> density. <jats:italic>Scn1b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> cortical pyramidal neurons had population\u2010specific changes in excitability and impaired I<jats:sub>Na<\/jats:sub> density. <jats:italic>Scn1b<\/jats:italic> deletion in PV\u00a0+\u00a0neurons resulted in 100% lethality, whereas deletion in Emx1\u00a0+\u00a0or Camk2a\u00a0+\u00a0neurons did not affect survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This work suggests that <jats:italic>SCN1B<\/jats:italic>\u2010linked DEE variants impact both excitatory and inhibitory neurons, leading to the increased severity of EIEE52 relative to other DEEs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51205","type":"journal-article","created":{"date-parts":[[2020,9,26]],"date-time":"2020-09-26T16:40:22Z","timestamp":1601138422000},"page":"2137-2149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Excitatory and inhibitory neuron defects in a mouse model of <i>Scn1b<\/i>\u2010linked EIEE52"],"prefix":"10.1002","volume":"7","author":[{"given":"Jacob M.","family":"Hull","sequence":"first","affiliation":[{"name":"Neuroscience Graduate Program University of Michigan Medical School Ann Arbor MI 48109 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A.","family":"O\u2019Malley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunling","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 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