Cellular and circuit function of Ndnf-expressing interneurons in a mouse model of a neurodevelopmental disorder

PROJECT SUMMARY/ABSTRACT Each year, 1 in 6 children are diagnosed with a neurodevelopmental disorder such as autism spectrum disorder, intellectual disability, or epilepsy. Such disorders severely impact the emotional, social, physical, and economic wellbeing of patients and their caregivers, and a poor understanding of the underlying pathophysiology of these disorders has slowed the discovery of effective therapies. There is evidence, however, that neurodevelopmental disorders as a class are associated with selective dysfunction of GABAergic inhibitory interneurons in the cerebral cortex. Dravet Syndrome, caused by pathogenic variants in the SCN1A gene encoding the Nav1.1 voltage-gated sodium channel a subunit, is a canonical example of a neurodevelopmental disorder caused by interneuron dysfunction, as interneurons in the neocortex preferentially rely on Nav1.1 for action potential generation and propagation. Importantly, cerebral cortical interneurons are a functionally heterogenous population; therefore, understanding the contribution of different classes of interneurons to microcircuit function in normal brain, and dysfunction in the setting of pathology, is essential for further elucidating the mechanisms of neurodevelopmental disorders. In this proposal, I will determine the function or dysfunction of the least studied major population of neocortical interneurons, those expressing Neuron-Derived Neurotrophic Factor (Ndnf), within cerebral cortical microcircuits in Dravet Syndrome. These cells are enriched in layer 1 of neocortex, where they are thought to play a role in sensory processing and regulating inhibitory tone in the cortex. Using a clinically-relevant and well-characterized mouse model of Dravet Syndrome, I will first establish the electrophysiologic, synaptic, and morphologic properties of Ndnf-expressing interneurons in Scn1a+/- mice relative to wild-type mice in vitro (Aim 1). I will then determine the behavior of these cells within cortical microcircuits in Scn1a+/- mice relative to wild-type in vivo using multiphoton imaging and optogenetic approaches (Aim 2). This proposal will not only provide novel data on an understudied interneuron subtype, both in health and disease, but also provide training in a suite of advanced electrophysiologic and optical techniques that will serve to train the applicant towards a future career as a physician-scientist studying circuit dysfunction in neurological disorders and development of new therapies and cures.