# Binding of synGAP to PDZ domains of PSD-95 and its role in Intellectual Disability and Autism Spectrum Disorders caused by synGAP haploinsufficiency

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $432,530

## Abstract

SynGAP Haploinsufficiency is the cause of ~2-5% of sporadic Intellectual Disability (ID) accompanied by
autism spectrum disorder (ASD) and/or epilepsy. SynGAP is specifically located postsynaptically and is located
in the postsynaptic density (PSD). It has a GTPase activating (GAP) domain that accelerates inactivation of Ras
and Rap. However, new evidence, including our own, suggests an additional activity that, when lost, may
contribute significantly to the pathology. We have shown that SynGAPα1 binds to all three PDZ domains of the
major PSD scaffold protein, PSD-95, and have measured its affinity for each PDZ domain. SynGAPα1 is
abundant in the PSD; its α1 isoform could occupy up to 15% of PSD95's PDZ domains in wild type animals and
thus compete with binding of other PDZ-domain ligands. We have shown that in synGAP+/- mice (an animal
model for synGAP haploinsufficiency), the amount of synGAP in the PSD is reduced and the amounts of other
PDZ-domain binding proteins are increased, including TARP-ɣ2,3,4, and 8, and LRRTM2, both of which are
AMPA-type glutamate receptor (AMPAR) chaperone proteins. This change in composition would increase the
excitatory/inhibitory balance of synapses onto neurons and contribute to abnormal brain function. Thus, we
postulate that reduction of binding of synGAP to PDZ domains of PSD-95 is a major contributor to the ID and
ASD observed in SynGAP Haploinsufficiency. We have found that phosphorylation by Ca2+/calmodulin-
dependent protein kinase II (CaMKII) decreases the affinity of synGAP for PDZ domains. We postulate that
phosphorylation of synGAP is important for reconfiguration of the PSD during early stages of induction of LTP.
In Aim One, we will enable quantitative tests of the hypothesis that binding of synGAP to PDZ domains
regulates the composition of the PSD by measuring the affinities between PDZ domains of PSD-95 and the
carboxyl terminal tails of TARP-ɣ2,3,4, and 8, LRRTM2, and NR2B. We will express soluble fusion proteins
containing the cytosolic carboxyl termini of each protein. To determine affinities for each PDZ domain, we will
use Biacore surface plasmon resonance detection of binding to recombinant PDZ domains by the “affinity in
solution” method that we perfected for use with synGAP. In Aim Two, we will construct computational
models in MCell to simulate equilibrium binding of synGAP and each of these proteins to PSD-95. The models
will make use of parameters measured in Aim One. We will construct models of in vitro experiments in order to
test their concepts and parameters by comparing simulated results to experimental results. We will then
construct spatially realistic models within reconstructed spine geometries to study how the spatial
arrangement and high densities of proteins in the spine influence competition among the proteins for binding
to PSD-95. In Aim Three, we will use cultured rodent neurons to test the hypothesis that phosphorylation of
synGAP drives acute changes in the composit...

## Key facts

- **NIH application ID:** 9881345
- **Project number:** 5R01MH115456-03
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** MARY B KENNEDY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,530
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881345

## Citation

> US National Institutes of Health, RePORTER application 9881345, Binding of synGAP to PDZ domains of PSD-95 and its role in Intellectual Disability and Autism Spectrum Disorders caused by synGAP haploinsufficiency (5R01MH115456-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881345. Licensed CC0.

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