# NMDAR Mutations & Neurodevelopmental Disorder: from Mechanism to Targeted Therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $336,475

## Abstract

ABSTRACT
 N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that mediate the slow
component of excitatory post-synaptic currents and play important roles in normal brain function. Genetic
variations in GRIN genes, which encode the GluN subunits, are linked to neurodevelopmental disorders,
including epileptic encephalopathy, autism, and intellectual disability, which carry devastating mental and
economic consequences for the individuals, their families, and society. Following the first report on disease-
causing GRIN variants in 2010, a large number of human variants (>300) in GRIN genes have been identified
in pediatric patients with various neurologic problems. Our studies in the previous funding cycle indicated that
similar phenotypes (i.e. seizures) could result from both gain-of-function (GoF) and loss-of-function variants
(LoF) in the same gene. Our work also revealed that different GRIN variants present differential sensitivity to
FDA-approved drugs, and there are divergent responses to the same treatment among three unrelated patients
hosting the same variant in “N of 1” trials. The proposed experiments will provide the first detailed evaluation
of circuit function following LoF and GoF NMDAR at different developmental stages, and address how the two
opposite effects on NMDARs might generate a similar phenotype. These studies will define a critical window in
which circuit connections relevant for aberrant activity are established, and will advance opportunities for
personalized medicine by suggesting new therapeutic strategies for mitigation of functional changes.
Specific Aim 1: Functional assessment of newly identified disease-associated GRIN variants and evaluation of
GRIN2A variants in the general population. We will analyze the functional properties of all newly published
and unpublished disease-associated GRIN variants in the understudied regions of the receptors. We will
determine the relationship between protein function and allelic frequency in healthy individuals, and evaluate
the idea that variation of intolerant genes can act as risk factors for neurological disorders.
Specific Aim 2: How does the loss of NMDAR activity promote network hyperexcitability and induce epileptic
phenotypes? We will evaluate in vivo knockin mice hosting two LoF variants and GluN2A knockout mice to
explore whether loss of NMDAR function reduces synaptic inhibition and leads to network hyperexcitability.
Specific Aim 3: What is the mechanism of gain-of-function GRIN variant-associated early-onset epileptic
encephalopathy? We will use in vivo knockin mouse models for three GoF GRIN variants to determine
whether enhanced NMDAR function drives seizures and early-onset epileptic encephalopathy.
Specific Aim 4: How can GRIN/NMDAR channelopathies best be treated? We will screen ~2,000 FDA-
approved drugs for their ability to rectify GRIN variant-induced hyperexcitability. We will evaluate actions of
FDA-approved drugs on transgenic mice t...

## Key facts

- **NIH application ID:** 10620814
- **Project number:** 5R01HD082373-08
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** HONGJIE YUAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $336,475
- **Award type:** 5
- **Project period:** 2015-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620814

## Citation

> US National Institutes of Health, RePORTER application 10620814, NMDAR Mutations & Neurodevelopmental Disorder: from Mechanism to Targeted Therapy (5R01HD082373-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10620814. Licensed CC0.

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