# CRCNS: Regulating AMPAR trapping and desensitization in the postsynaptic density

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $305,901

## Abstract

The overall goal of this project is in the spirit of Richard Feynman -- "What I cannot create, I do not
understand". Over the past decade many laboratories have reported new insights on synaptic transmission
properties, based on electrophysiology, imaging, or biochemistry experiments. But the precise impact on
synaptic properties of the various measured parameters such as molecular organization, mobility, or
molecular interactions has remained elusive. Here we propose to overcome this problem through a synergy
between the phenomenological descriptions of AMPAR organization based on super-resolution imaging
techniques, the identification of the core of such organization with quantitative biochemistry, and quantitative
biophysical modeling of synaptic transmission. The resulting model will deliver testable predictions of
synaptic transmission properties that we will directly test with electrophysiological recordings. The ultimate
result will be a reliable model based on brand new knowledge of synaptic organization and function at the
nanoscale.
 The project will be divided into three Aims. In Aim 1 we will implement in an existing model three main
modifications regarding newly available knowledge on AMPAR properties: (i) in situ constraints for the
activation/inactivation kinetic rate constants of the tetrameric concerted opening model of AMPAR including
the effect of AMPAR/TARP interaction on AMPAR gating properties; (ii) the tight organization of AMPAR in
nanoclusters as reported recently by using super-resolution techniques; (iii) The lateral diffusion of AMPAR
which has been measured with live single particle techniques. In Aim 2 we will measure the biochemical
on/off rate and cross-affinity of the three main proteins responsible for AMPAR organization: PSD95, the
TARPs and synGAP. At the end of this Aim, the model should be able to perfectly simulate synaptic
transmission recorded at a neuron, both in term of kinetics, amplitude and variability, by taking into account
the lateral mobility of AMPAR complex and PSD95 slot occupancy as a function of the determined affinity.
Finally in Aim 3, we wfll validate the model and the hypothesis by modifying either the expression level of
synGAP or the relative affinity of synGAP or TARP for PSD95, and then compare effect of such changes on
AM PAR organization and dynamic properties and on synaptic transmission properties with the model
predictions.
RELEVANCE (See instructions):
The proposed work involves study of the molecular mechanisms that control synaptic plasticity and their role
in mental illness, a Strategic Research Priority of the NIMH. The work will help to clarify the function of the
protein synGAP in CNS synapses and will impact Public Health as SynGAP has been found to be mutated
in -1 % of children presenting a cognitive disability accompanied by autism and or epilepsy.

## Key facts

- **NIH application ID:** 9967107
- **Project number:** 5R01MH115556-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** TERRENCE J SEJNOWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $305,901
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967107

## Citation

> US National Institutes of Health, RePORTER application 9967107, CRCNS: Regulating AMPAR trapping and desensitization in the postsynaptic density (5R01MH115556-04). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9967107. Licensed CC0.

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