title: Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility.
abstract: Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Electrophysiological analyses of DS and GEFS+ mouse models have led to the hypothesis that SCN1A mutations reduce the excitability of inhibitory cortical and hippocampal interneurons. To more directly examine the relative contribution of inhibitory interneurons and excitatory pyramidal cells to SCN1A-derived epilepsy, we first compared the expression of Nav1.1 in inhibitory parvalbumin (PV) interneurons and excitatory neurons from P22 mice using fluorescent immunohistochemistry. In the hippocampus and neocortex, 69% of Nav1.1 immunoreactive neurons were also positive for PV. In contrast, 13% and 5% of Nav1.1 positive cells in the hippocampus and neocortex, respectively, were found to co-localize with excitatory cells identified by CaMK2α immunoreactivity. Next, we reduced the expression of Scn1a in either a subset of interneurons (mainly PV interneurons) or excitatory cells by crossing mice heterozygous for a floxed Scn1a allele to either the Ppp1r2-Cre or EMX1-Cre transgenic lines, respectively. The inactivation of one Scn1a allele in interneurons of the neocortex and hippocampus was sufficient to reduce thresholds to flurothyl- and hyperthermia-induced seizures, whereas thresholds were unaltered following inactivation in excitatory cells. Reduced interneuron Scn1a expression also resulted in the generation of spontaneous seizures. These findings provide direct evidence for an important role of PV interneurons in the pathogenesis of Scn1a-derived epilepsies.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30022, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Dutton
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30022, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Makinson
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30022, USA.
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Papale
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30022, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Shankar
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30022, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Balakrishnan
authors.affiliation: Unit on Genetics of Cognition and Behavior, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Kazu
authors.initials: K
authors.lastname: Nakazawa
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30022, USA. Electronic address: aescayg@emory.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004198:Disease Susceptibility / Q000378:metabolism; D005334:Fever; D005481:Flurothyl; D006624:Hippocampus / Q000503:physiopathology; D007395:Interneurons / Q000502:physiology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000235:genetics; D019579:Neocortex / Q000503:physiopathology; D009433:Neural Inhibition / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D017966:Pyramidal Cells / Q000503:physiopathology; D012640:Seizures / Q000503:physiopathology*; D003294:Seizures, Febrile / Q000503:physiopathology*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D010320:Parvalbumins; C568249:Scn1a protein, mouse; D005481:Flurothyl; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse