# Molecular mechanisms of abnormal dendritic spine development and function in human neurons with TSC2 disease mutations

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $407,645

## Abstract

Project Summary/Abstract
Growing evidence suggests that patients with Tuberous Sclerosis Complex (TSC), like other neuro-
developmental disorders, have dysfunctional synaptic connections. These defects in neuronal connectivity
likely contribute to symptoms of TSC, such as cognitive deficits, autism and epilepsy. However, defective
synaptic development and function by human neurons has only been suggested from animal model studies
and a few recent studies using human neurons, which have led to conflicting reports. To directly address these
fundamental questions and help resolve conflicting findings, we will compare the development and function of
human cortical neuron synapses of TSC patient neurons with their corrected control counterparts. Cortical
neurons are differentiated from human induced pluripotent stem cells (hiPSCs) generated from TSC patient
cells and their engineered isogenic counterparts. Using a series of morphometric and molecular signaling
assays, we will examine the structure and function of pre- and post-synaptic compartments of control and
TSC2 mutant synapses in mixed genotype cultures. Our surprising recent findings suggest that TSC2 functions
independent of mTORC in growth cones to directly regulate the cytoskeleton and control axon guidance,
prompting us to consider similar mechanisms may function in dendritic spine development. We will also test
how synaptic transmission and network activity may be altered in TSC2 patient neurons. Over the long term,
we believe our research may help identify key druggable targets in patients with TSC.

## Key facts

- **NIH application ID:** 10360715
- **Project number:** 1R21NS125419-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Timothy M Gomez
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $407,645
- **Award type:** 1
- **Project period:** 2021-09-20 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360715

## Citation

> US National Institutes of Health, RePORTER application 10360715, Molecular mechanisms of abnormal dendritic spine development and function in human neurons with TSC2 disease mutations (1R21NS125419-01). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10360715. Licensed CC0.

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