# TSC and sensory processing

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $209,375

## Abstract

The goal of this proposal is to identify how abnormalities of brain development in monogenic
disorders involving the PI3K-mTOR pathway (e.g., tuberous sclerosis complex [TSC]) lead to
alterations in circuit and in information processing. TSC is a classical disorder of the mTOR
signaling pathway due to second-hit somatic mutations in TSC1 or TSC2 leading to mTOR
hyperactivity and developmental malformations associated with seizures and neurological
deficits. 50-60% of children with TSC have severe cognitive deficits and autism accompanied with
abnormal sensory processing. Published work from our lab identified a combination of molecular
and cellular alterations in murine neurons with hyperactive mTOR. These alterations include
neuron misplacement and dysmorphogenesis that are conserved across cortical regions and
between mice and humans. However, the impact of these defects on circuit formation and
information processing, and the dependence on mTOR and downstream pathways at the circuit
level remain unclear. Here, we propose to use the mouse barrel cortex as a well-established
model system to start addressing the link between neuronal abnormalities and alterations in
circuitry and sensory processing. Building from our previous findings, we hypothesize that
dysmorphogenesis of layer (L) 4 barrel cortex neurons in TSC contributes to mTOR-dependent
abnormalities in circuitry, functional connectivity, and sensory responses. We have the following
two aims: (1) To test the hypothesis that mTOR hyperactivity in L4 neurons alters barrel circuitry
and functional connectivity. (2) To test the hypothesis that reducing mTOR activity during a brief
critical window and normalizing two downstream pathways prevent abnormalities in circuit and
sensory responses in TSC condition. To address these aims, we will use in utero electroporation
to express RhebCA and generate humanized Tsc1 mutations using CRISPR/Cas9 in L4 neurons
of the barrel cortex.

## Key facts

- **NIH application ID:** 10017331
- **Project number:** 5R21NS110407-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Angelique Bordey
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2019-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017331

## Citation

> US National Institutes of Health, RePORTER application 10017331, TSC and sensory processing (5R21NS110407-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10017331. Licensed CC0.

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