# The role of Syngap1 in striatal physiology and behavior

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $431,750

## Abstract

PROJECT SUMMARY
 SYNGAP1-related non-syndromic intellectual disability is a neurodevelopmental disorder
caused by mutations in the SYNGAP1 gene. SYNGAP1 encodes the protein SynGAP, which is a highly
abundant protein in the post-synaptic density of excitatory synapses. At synapses, SynGAP functions to
repress downstream NMDAR signaling and AMPAR trafficking through its inhibition of small GTPases.
Translocation of SynGAP out of the post-synaptic density is required to allow NMDAR-dependent long-
term potentiation (LTP). In the absence of SynGAP, NMDAR-dependent plasticity is unrestrained
leading to alterations in synapse strength, spine structure, and plasticity. While the functions of
SynGAP have been nearly exclusively studied in the cortex and hippocampus, the striatum also
exhibits high levels of SynGAP expression. Striatal projection neurons are GABA-ergic neurons
covered in a dense array of dendritic spines that receive excitatory input from multiple cortical areas.
SynGAP is therefore positioned to play a key role in gating synaptic transmission and plasticity at
corticostriatal synapses. Despite this, SynGAP’s functions in striatal synaptic physiology have not yet
been defined. Moreover, several of the major symptoms of SYNGAP1 disorder likely involve striatal
pathophysiology including autism spectrum disorder, obsessive-compulsive behavior, motor
developmental delay, hyperexcitability, and other behavioral problems. In this exploratory study, we will
elucidate the consequences of SynGAP loss on striatal synaptic function and determine whether loss of
SynGAP from striatal neurons is sufficient to induce behavioral alterations relevant for SYNGAP1
disorder. Specifically, in Aim 1 we will determine how loss of SynGAP impacts corticostriatal synaptic
transmission and plasticity. In addition, we will use advanced imaging approaches to investigate how
SynGAP deficiency affects dendritic spine number and morphology. In Aim 2, we will determine
whether deletion of Syngap1 from specific striatal cell types is sufficient to alter motor behaviors, habit
learning, and cognitive flexibility. We will further test whether restoration of SynGAP expression only in
striatal projection neurons is capable of preventing behavioral abnormalities using a genetic rescue
strategy. Together, this work will provide an essential starting point for understanding SynGAP’s
functions at striatal synapses and identify the striatal cell type(s) most relevant for the manifestations of
SYNGAP1-related disorders.

## Key facts

- **NIH application ID:** 10042425
- **Project number:** 1R21MH123778-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Helen S. Bateup
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2020-05-06 → 2023-05-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042425

## Citation

> US National Institutes of Health, RePORTER application 10042425, The role of Syngap1 in striatal physiology and behavior (1R21MH123778-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10042425. Licensed CC0.

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