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NIH grant 1R21NS147529-01A1: VIP Interneuron Dysfunction in Tuberous Sclerosis Complex
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Shane R Crandall. Award: $431750.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY
This project will investigate how deleting the Tsc1 gene impacts vasoactive intestinal peptide (VIP) disinhibitory
circuits and the function of the medial prefrontal cortex (mPFC). The TSC1 and TSC2 genes play a critical role
in typical neurodevelopment. Mutations in these genes can lead to Tuberous Sclerosis Complex (TSC), a
multisystem disorder that often results in severe neurological issues like epilepsy and other behavioral and
cognitive difficulties. The TSC1/2 protein complex is essential for inhibiting mechanistic target of rapamycin
complex 1 (mTORC1) signaling, and disruptions can lead to atypical growth and development. Frontal
neocortical malformations are common in individuals with TSC, significantly affecting synaptic connectivity and
neural dynamics. Connecting these neurodevelopmental changes to relevant circuit phenotypes is critical for
enhancing our understanding of how TSC1/2 mutations contribute to the neurobiology of TSC and related
neurodevelopmental disorders.
VIP interneurons play a crucial role in regulating cortical network dynamics in response to inputs by disinhibiting
excitatory pyramidal neurons, a general circuit principle observed throughout the neocortex, including the mPFC.
Preliminary data from our group indicate that this disinhibitory circuit is significantly disrupted in a TSC mouse
model. Thus, the central goal of this exploratory R21 grant is to further connect neurodevelopmental defects to
changes in VIP synaptic circuitry in the mPFC and to begin testing the hypothesis that VIP-specific Tsc1 loss
alters neurophysiology and behavior. We address this goal in two aims. Aim 1 will utilize well-established mouse
lines and in vitro electrophysiology to determine the impact of conditional Tsc1 loss on the general organization
and function of electrical and chemical synapses within VIP disinhibitory circuits in the mPFC. Aim 2 will use in
vivo electrophysiological methods and targeted behavioral tests to test the hypothesis that Tsc1 deletion in VIP
neurons causes abnormal neural activity and behavior. This project will provide much-needed insight into how
developmental phenotypes caused by Tsc1/2 deficiencies alter circuit formation and function. Such information
will be essential for developing safe and effective treatments for TSC and improving the lives of those affected
by this complex disorder.document fetched 2026-09-20 02:42