# Cellular and molecular mechanisms disrupted in 22q13 deletion syndrome and autism

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

Mutations in genes encoding synaptic proteins and impaired functional brain connectivity are emerging
as common deficits associated with autism spectrum disorders (ASDs). However, how mutated synaptic
proteins affect the properties of human neurons at the cellular and molecular levels to cause abnormal brain
connections remains an important unanswered question. Addressing this question is essential for
understanding the etiology and pathology of ASDs and developing novel and effective therapeutic strategies
for patients. The PI previously demonstrated that SHANK3-deficient human cortical neurons derived from
induced pluripotent stem cells (iPSCs), generated from 22q13 deletion syndrome patients with autism, have
severely impaired intrinsic excitability and excitatory synaptic transmission. However, how these two
phenotypes develop and affect neuronal connectivity in the brain remain unknown. The main goal of this
project is to elucidate the cellular and molecular mechanisms responsible for development of synaptic and
connectivity deficits in SHANK3-deficient human neurons. SHANK3 is a scaffolding protein expressed at
excitatory synapses that have been frequently found to be mutated or deleted in individuals with autism and
intellectual disability. The central hypothesis of this project is that synaptic deficits in SHANK3-deficient human
neurons develop as a result of elevated electrical activity and activity-mediated weakening and elimination of
excitatory synapses. This hypothesis is strongly supported by the preliminary data obtained in the PI's
laboratory. The following Specific Aims are formulated to test this hypothesis: 1) Determine the role of elevated
electrical activity in development of synaptic deficits in SHANK3-deficient human neurons; 2) Determine the
role of ARC in development of synaptic deficits in SHANK3-deficient human neurons; and 3) Determine how
loss of SHANK3 in human neurons impacts synaptic inputs onto these neurons in vivo. Under these aims, the
properties of human cortical neurons generated from novel, precisely genetically-engineered stem cell lines will
be investigated using electrophysiology, imaging, and biochemistry techniques in vitro and upon engraftment
into the mouse brain. The proposed research is significant because it is expected to substantially advance
understanding of the molecular, cellular, and circuitry mechanisms disrupted in autism and intellectual
disability, and guide the development of novel therapeutic strategies for patients.

## Key facts

- **NIH application ID:** 10084752
- **Project number:** 5R01MH113670-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Oleksandr Shcheglovitov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084752

## Citation

> US National Institutes of Health, RePORTER application 10084752, Cellular and molecular mechanisms disrupted in 22q13 deletion syndrome and autism (5R01MH113670-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10084752. Licensed CC0.

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