Project Grant R15NS153291

The National Institute of Neurological Disorders and Stroke awarded Miami University $539,920 on September 5, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate how TSC1 loss disrupts Purkinje neuron axon initial segment organization and cerebellar function in autism spectrum disorder.

The research examines the cellular mechanisms by which TSC1 deletion in Purkinje neurons alters axon initial segment function and intrinsic firing through three specific aims. Aim 1 tests whether TSC1 deletion impairs Purkinje neuron firing through axon initial segment dysfunction using patch clamp electrophysiology, dynamic clamp rescue strategies, and quantitative immunofluorescence of axon initial segment proteins. Aim 2 determines whether Purkinje neuron excitability and axon initial segment phenotypes caused by TSC1 deletion are mediated by mTORC1 rather than mTORC2 signaling using neuron-targeted viral knockdown approaches and assessing molecular, electrophysiological, and behavioral outcomes. Aim 3 defines the mechanism underlying ankyrin-G loss by distinguishing among reduced ANK3 transcription, increased axon initial segment scaffold turnover, or increased proteolysis through transcript profiling from sorted Purkinje neurons and quantitative analysis.

Performance of work occurs in Oxford, Ohio. The period of performance extends from the award date through August 31, 2029. This is a project grant, an assistance type under NINDS extramural research funding.