# Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $397,500

## Abstract

PROJECT SUMMARY
Despite increasing knowledge of the genetic underpinnings of autism risk, the specific pathogenic mechanisms
underlying the emergence of motor and cognitive deficits in autism spectrum disorders (ASD) remain unclear.
Recent imaging and genetic studies have pointed to corticostriatal dysfunction has a prevalent pathophysiology
in ASD. In particular, hypertrophy and abnormal functional connectivity of prefrontal cortex (PFC) and
dorsomedial striatum (DMS) have been reported in multiple autistic individuals, providing a potential
neuropathological substrate for the repetitive behaviors and social deficits associated with autism. Our
laboratory has shown that mice with loss of function deletions in SHANK3 (Shank3B-/-), a highly penetrant
monogenic cause of autism, exhibit hyperactivity and abnormal patterns of connectivity in corticostriatal circuits
during postnatal development. Behavioral deficits in these animals also emerge during these early
developmental periods, suggesting that early corticostriatal dysfunction might be an important pathogenic
mechanism in SHANK3 associated disorders. Here we propose to further characterize how striatal circuit
development is impaired by loss of Shank3 and identify the specific corticostriatal pathways affected in these
conditions (Aim1). In addition, using recently developed conditional transgenic mice that allow cell-specific
manipulation of Shank3 expression we will dissect the specific mechanisms leading to corticostriatal
connectivity abnormalities (Aim 2). In addition, using new molecular strategies that normalize early excitatory
drive in striatal neurons, we will determine the pathogenic role of early striatal circuit dysfunction in the
emergence of maladaptive behaviors in Shank3B-/- mice (Aim 3). This work will advance our understanding of
the basic mechanisms and developmental rules regulating the maturation of corticostriatal circuits and provide
important insights into the pathogenesis of ASD and other neurodevelopmental disorders with early activity
imbalances in corticostriatal circuits.

## Key facts

- **NIH application ID:** 10735802
- **Project number:** 5R01MH124695-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Rui Peixoto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10735802

## Citation

> US National Institutes of Health, RePORTER application 10735802, Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice (5R01MH124695-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10735802. Licensed CC0.

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