# The impact of Tsc-mTOR signaling on basal ganglia function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2022 · $320,573

## Abstract

PROJECT SUMMARY
 Tuberous Sclerosis Complex is a neurodevelopmental disorder caused by mutations in the
TSC1 or 2 genes that encode negative regulators of mTOR complex 1 signaling. TSC is associated
with a high prevalence of autism spectrum disorder (ASD) and other neuropsychiatric conditions, which
are debilitating for patients and caregivers. Despite their prevalence in TSC, relatively little is known
about the neurobiology of these manifestations including the cell types responsible. We propose that a
core aspect of ASD, repetitive, inflexible patterns of behavior, is caused by synaptic changes in the
basal ganglia, a brain region responsible for the selection and learning of appropriate actions. Here we
will investigate this in the context of TSC by determining how mutations in Tsc1 affect the cellular
physiology and behavioral output of neurons comprising key basal ganglia circuits. To isolate specific
cell types, we will use genetic mouse models in which Tsc1 is selectively deleted from defined cell
populations. The experiments in Aim 1 will determine how Tsc1 loss affects synaptic transmission and
plasticity in the two classes of striatal projection neurons that initiate the primary output pathways of the
basal ganglia. We will test the idea that increased cortical synaptic drive of direct pathway striatal
neurons leads to altered learning and increased propensity for motor habit formation. Striatal activity is
dynamically regulated by dopamine signaling, which exerts powerful control over behavior. In Aim 2, we
will determine how selective deletion of Tsc1 from dopamine neurons affect their physiology and output.
We will test the hypothesis that loss of Tsc1 causes hypofunctional striatal dopamine signaling leading
to impaired cognitive flexibility in reversal learning tasks. This strategy represents a key step towards
dissecting the cellular and circuit basis of TSC, and may ultimately inform new therapeutic strategies for
this and related ASDs.

## Key facts

- **NIH application ID:** 10371870
- **Project number:** 5R01NS105634-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Helen S. Bateup
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $320,573
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371870

## Citation

> US National Institutes of Health, RePORTER application 10371870, The impact of Tsc-mTOR signaling on basal ganglia function (5R01NS105634-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371870. Licensed CC0.

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