# The role of NMDA receptor co-agonist site occupancy in synaptic plasticity

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $179,357

## Abstract

The brain is made up of billions of neurons that connect via trillions of synapses, the chemical junction between
two neurons. Proper development and regulation of these synapses is crucial for the proper functioning of the
brain. Indeed, synaptic dysfunction is thought to be the primary basis of many brain diseases, including
Alzheimer’s disease, schizophrenia, autism, epilepsy, addiction, and chronic pain. In the brain, the majority of
synapses important for learning and memory are chemically stimulated by glutamate. Glutamate activates a
specific protein known as the N-methyl-D-aspartate (NMDA) receptor that plays an essential role in proper brain
development and synapse functioning. However, two fundamental properties of the NMDA receptor remain
elusive; 1) why do NMDA receptors require two chemical signals, glutamate and glycine, for activation? And 2)
how can NMDA receptors regulate both the strengthening and weakening of synapses during learning and
memory? Understanding these two critical functions of NMDA receptors, in addition to contributing to our basic
knowledge of neurobiology, may also point to a therapeutic strategy that will directly target and possibly even
reverse the core synaptic changes that cause brain disease states such as addiction and chronic pain. The goal of
this proposal is to understand how NMDA receptor co-agonism influences synaptic plasticity. The central
hypothesis is that co-agonist site occupancy dictates the directionality of synaptic plasticity. Recent evidence by
myself and others has shown that long-term depression (LTD) does not actually require ion flow through the
NMDA receptor channel, but requires only glutamate binding. These results are contrary to the long-standing
view that long-term potentiation (LTP) was due to rapid, large levels of calcium influx through the receptor, and
LTD was mediated by low level, repetitive increases in calcium. Instead, these new results suggest that NMDA
receptors invoke intracellular signaling solely due to conformational changes upon agonist binding. Building
upon these new findings, I have developed a model that predicts a fundamental role of glycine/D-serine site
occupancy as a direct regulator of the directionality of synaptic plasticity. This model allows for predictions that
can be rigorously tested with pharmacological approaches in slice electrophysiology (Aim 1) and the single-cell
genetic manipulations (Aim 2) regularly used in my laboratory. Validation of this model will open a new frontier
of NMDA receptor and synapse biology that will have a significant impact on many areas of neuroscience and
may lead to the development of novel approaches to modify synaptic plasticity for the treatment of
neuropsychiatric diseases.

## Key facts

- **NIH application ID:** 9830672
- **Project number:** 5R21MH116315-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** John Alan Gray
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $179,357
- **Award type:** 5
- **Project period:** 2018-12-03 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830672

## Citation

> US National Institutes of Health, RePORTER application 9830672, The role of NMDA receptor co-agonist site occupancy in synaptic plasticity (5R21MH116315-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830672. Licensed CC0.

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