Medial septum parvalbumin-expressing inhibitory neurons are impaired in a mouse model of Dravet Syndrome

Summary Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic variants in the SCN1A gene, which encodes the voltage-gated sodium channel Na v 1.1 α subunit. Experiments in animal models of DS – including the haploinsufficient Scn1a +/- mouse – have identified impaired excitability of interneurons in the hippocampus and neocortex; this is thought to underlie the treatment-resistant epilepsy that is a prominent feature of the DS phenotype. However, additional brain structures, such as the medial septum (MS), also express SCN1A . The medial septum is known to play an important role in cognitive function and thus may contribute to the intellectual impairment that also characterizes DS. In this study, we employed whole cell patch clamp recordings in acute brain slices to characterize the electrophysiological properties of MS neurons in Scn1a +/- mice versus age-matched wild-type littermate controls. We found no discernible genotype-related differences in MS cholinergic (ChAT) neurons, but significant dysfunction within MS parvalbumin-expressing (PV) inhibitory neurons in Scn1a +/- mice. We further identified heterogeneity of firing patterns among MS PV neurons, and additional genotype differences in the proportion of subtype representation. These results confirm that the MS is an additional locus of pathology in DS, that may contribute to co- morbidities such as cognitive impairment.