Ndnf interneuron excitability is spared in a mouse model of Dravet syndrome

Abstract

Dravet syndrome (DS) is a neurodevelopmental disorder characterized by epilepsy, developmental delay/intellectual disability, and features of autism spectrum disorder, caused by heterozygous loss-of-function variants inSCN1Aencoding the voltage-gated sodium channel α subunit Nav1.1. The dominant model of DS pathogenesis is the “interneuron hypothesis,” whereby GABAergic interneurons (INs) express and preferentially rely on Nav1.1-containing sodium channels for action potential generation. This has been shown for three of the major subclasses of cerebral cortex GABAergic INs: those expressing parvalbumin, somatostatin, and vasoactive intestinal peptide. Here, we define the function of a fourth major subclass of INs expressing Neuron-derived neurotrophic factor (Ndnf) in male and female DS (Scn1a+/-) mice. Patch clamp electrophysiological recordings of Ndnf-INs in brain slices fromScn1a+/- mice and wild-type controls reveal normal intrinsic membrane properties, properties of action potential generation and repetitive firing, and synaptic transmission across development. Immunohistochemistry shows that Nav1.1 is strongly expressed at the axon initial segment (AIS) of parvalbumin expressing INs but is absent at the Ndnf-IN AIS.Invivo two-photon calcium imaging demonstrates that Ndnf-INs inScn1a+/-mice are recruited similarly to wild-type controls during arousal. These results suggest that Ndnf-INs are the only major IN subclass that does not prominently rely on Nav1.1 for action potential generation, and thus retain their excitability in DS. Discovery of a major IN subclass with preserved function in theScn1a+/-mouse model adds further complexity to the “interneuron hypothesis” and highlights the importance of considering cell type heterogeneity when investigating mechanisms underlying neurodevelopmental disorders.Significance StatementDravet syndrome is a severe neurodevelopmental disorder characterized by epilepsy, developmental impairment, and autism spectrum disorder, due to mutations in the geneSCN1Aencoding the voltage-gated sodium channel subunit Nav1.1. Prior work has demonstrated impaired spike generation across subtypes of GABAergic cerebral cortex inhibitory interneurons in Dravet syndrome mouse models due to prominent expression of Nav1.1 in interneurons vs. excitatory principal cells. Here, we show that a previously unexamined interneuron subtype – neocortical layer 1 interneurons expressing neuron-derived neurotrophic factor (Ndnf) – are unique among interneurons in that they do not express Nav1.1 and exhibit normal electrical excitability in a mouse model of Dravet syndrome. This work highlights the complex cellular and circuit mechanisms underlying pathogenesis of this neurodevelopmental disorder.