# Characterization of SynGAP Mutations in Human Cognitive Disorders

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $528,913

## Abstract

Project Summary
Recent genome-wide association studies of Intellectual disability (ID), Autism spectrum disorder (ASD) and
Schizophrenia (SCZ) have improved our understanding of the molecular and cellular basis of human cognitive
diseases. Functional categorization of these genes has revealed a significant enrichment of mutations affecting
glutamatergic synapse structure and function. One protein that has been shown to regulate glutamatergic
synapses is SynGAP, a RasGAP that is a critical negative regulator of spine morphogenesis and synaptic
plasticity via Ras-ERK and protein synthesis-dependent signaling pathways. De Novo deleterious SYNGAP
mutations are estimated to account for approximately 1% of ID cases and are highly comorbid with ASD.
SYNGAP variants have also been found to be a significant risk factor in other neuropsychiatric disorders
including SCZ and bipolar disorder (BP). We recently identified SynGAP as one of the most potent regulators
of synaptic size and/or number using a high-throughput screen of 200 SCZ-associated risk genes. In addition,
we found that ID/ASD-associated SynGAP mutations also affect synaptic structure and function. These data
support the notion that human SynGAP mutations might alter synaptic transmission and plasticity. To
determine how disease-associated SynGAP mutations impact synaptic pathophysiology and behavior, we will
first characterize the effect of SYNGAP disease risk variants on synapse structure and function using a
combination of approaches including real time imaging, biochemical and electrophysiological techniques. Next,
we will use CRISPR/Cas9 genome editing to generate mouse models carrying SynGAP mutations that
precisely mimic human disease risk variants of SynGAP. With these mice we will determine whether they have
differential plasticity, circuit and behavioral phenotypes. Finally, we will perform mechanism based drug
screens to target disrupted SynGAP-regulated signal transduction pathways to discover small molecule(s) that
can ameliorate synaptic and behavioral deficits. This proposed project would be the first systematic
investigation of disease-associated SynGAP mutations on synaptic pathophysiology and animal behavior.
These studies will allow us to gain insight into mechanisms underlying SynGAP-associated diseases and pave
the way for novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10094253
- **Project number:** 5R01MH112151-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Richard L Huganir
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $528,913
- **Award type:** 5
- **Project period:** 2017-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094253

## Citation

> US National Institutes of Health, RePORTER application 10094253, Characterization of SynGAP Mutations in Human Cognitive Disorders (5R01MH112151-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10094253. Licensed CC0.

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