The role of cerebellar inhibitory interneurons in neurodevelopmental disorders (360G-Wellcome-224619_Z_21_Z)

Cerebellar anomalies represent the most consistent defect in many prevalent neuropsychiatric disorders such as autism. Imbalance in excitatory: inhibitory (E:I) neurons has been implicated in the pathogenesis of these disorders in the cerebral cortex yet the precise role of E:I imbalance in cerebellar associated disease has been largely overlooked. We recently identified a novel human genetic disorder associated with cerebellar hypoplasia and autistic features caused by mutation in PRDM13 and subsequently discovered a novel function for Prdm13 in cerebellar GABAergic interneuron fate specification. Little is currently known about what regulates GABAergic interneuron specification or how these neurons function to influence behaviour. I will identify central regulators of inhibitory cell specification in the cerebellum, and the underlying molecular mechanisms and consequences of altered specification on circuit function. I will combine mouse genetics, single cell transcriptomics and state-of-the-art in vivo functional imaging and electrophysiology to address the following goals: (1) Characterise molecular mechanisms driving specification and diversification of cerebellar inhibitory interneurons. (2) Identify how Prdm13 regulates inhibitory fate specification. (3) Determine consequences of Prdm13 disruption on the functional properties of cerebellar interneurons.