# Molecular and circuitry mechanism underlying autism behaviors in Shank3 mouse models

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $706,078

## Abstract

Molecular and circuitry mechanism underlying autism behaviors in Shank3 mouse models
ABSTRACT:
While there has been significant progress in identifying the genetic defects in individuals with autism spectrum
disorders (ASD), the molecular heterogeneity fails to provide mechanistic insights into how genetic defects result
in ASD. It has been proposed that defects in >100 genes strongly implicated in ASD converge onto a few distinct
molecular pathways and contribute to the shared neural circuits supporting ASD. To identify the underlying
mechaniams we adopted the RDoC matrix to establish links within a Gene-Molecule-Circuit-Behavior (GMCB)
axis for SHANK3-related ASD. Defects in SHANK3 are found in ~2% of individuals with ASD, and the most
common defect (>95%) is deletion of the entire SHANK3 gene. In contrast to the 14 Shank3 isoform-specific
knockout (KO) mice, we have generated a unique Shank3 complete-KO mouse by conventional or conditional
deletion of exons 4-22 (Δe4-22 or e4-22flox). The ∆e4-22 mice display robust behaviors that recapitulate core
features of ASD associated with SHANK3-deficiency in humans. We recently generated a new mouse with a
Homer1 binding mutation (SH3-PL) in Shank3 that permits us to probe mechanistic links within the RDoC matrix.
In ∆e4-22 mice functions of cortical/striatal synapses are impaired and functional connectivity is abnormal in the
nucleus acumens (NAC) -associated axis. Results from striatal- and cortical-specific Shank3 e4-22flox mice and
viral-mediated SHANK3 rescue suggest distinct roles for the NAC and cortical circuits in social, instrumental,
and repetitive behaviors. Molecularly, Homer1-mGluR5 scaffolds are altered in the striatum but not cortex, while
NMDA receptors are reduced in cortex but not striata of Δe4-22 mice. Our central hypothesis is that abnormal
social and repetitive behaviors in Shank3 mice are caused by alterations in Homer1-mGluR5 scaffolds in a NAC
circuit and in NMDAR functions in a cortical circuit, respectively. These molecular- and circuit-specific aberrations
may represent a convergent molecular pathway with shared neural circuits that underlie the abnormalities in
social, instrumental, and repetitive behaviors. The specific objective of this proposal is to use the RDoC matrix
as guide to analyze mechanisms within a GMCB axis using our Shank3 complete-KO and the new SH3PL mice.
RELEVANCE:
These results will provide unique insights into the roles that Homer1-mGluR5 scaffolds and NMDARs play in
ASD-like behaviors by establishing a convergent point of genes, molecular pathways, and neural circuits that
may be amenable to targeted treatments for ASD.

## Key facts

- **NIH application ID:** 9857662
- **Project number:** 5R01MH117289-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YONG-HUI JIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $706,078
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857662

## Citation

> US National Institutes of Health, RePORTER application 9857662, Molecular and circuitry mechanism underlying autism behaviors in Shank3 mouse models (5R01MH117289-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857662. Licensed CC0.

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