# Loss of Grin2a Promotes Hippocampal Hyperexcitability and Epileptiform Activity

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $43,238

## Abstract

PROJECT SUMMARY/ABSTRACT:
 De novo mutations in the GRIN2A gene, which encodes the GluN2A subunit of the N-methyl-D-aspartate
receptor (NMDAR), are linked to several forms of epileptic encephalopathy (EE). EE is a group of devastating
epilepsies, which often involve intractable seizures and different brain abnormalities. The prognosis for EE
patients is poor, partly due to inadequate pharmacological options that dampen symptoms, but have little ability
to rectify underlying aberrant neuronal circuitry. In addition, children with EE often require around-the-clock care,
placing a heavy social and financial burden on primary caregivers, making the need for early intervention with
circuitry-correcting therapeutics urgent and necessary. Here, I propose experiments that explore the cellular
mechanisms driving epileptiform activity in patients with loss-of-function (LoF) GRIN2A mutations, a group of
genetic variants that reduce the function or cell surface expression of GluN2A-containing NMDARs. Whole
exome sequencing revealed that multiple patients with EE have de novo mutations in GRIN2A, with a prevalence
of roughly 1 in 80,000. Evaluation for functional activity has revealed that 56% of epilepsy-related GRIN2A
mutations are LoF variants, displaying diminished receptor function and/or decreased surface expression. These
results are intriguing as one might hypothesize that the loss of excitatory synaptic GluN2A subunit would
decrease excitability, rather than promote epileptiform activity.
 To understand how diminished GluN2A function/expression can promote compensatory alterations that
increase excitability, I will use Grin2a +/- and -/- mice as a model for loss-of-function GRIN2A variants.
Preliminary behavioral data indicate that Grin2a -/- (2AKO) mice have a lower threshold for febrile-induced
seizures compared to wildtype (WT) mice. In adult brain slices, 2AKO mice exhibit an increased frequency of
epileptiform burst-firing activity in the CA1 region of the hippocampus compared to WT mice. These data indicate
that the loss of GluN2A activity is sufficient to drive an epileptic phenotype, as observed in human patients with
heterozygous LoF GRIN2A mutations. Taken together, these data suggest that 2AKO mice have an altered
excitatory-to-inhibitory balance. Therefore, I hypothesize that epileptiform activity in 2AKO mice is: 1)
dependent on a critical developmental window, 2) may be due to changes in postsynaptic receptor expression
and hippocampal connectivity, and 3) could be modulated by aberrant forms of synaptic plasticity. Information
on how and when the imbalance in excitation/inhibition is generated will help advance a cellular and temporal
understanding on the mechanisms involved in epileptogenesis in LoF GRIN2A patients. Thus, these experiments
could help guide specific anti-epileptic treatment options for LoF GRIN2A patients suffering from EE. Moreover,
if aspects of epileptogenesis are shared across the spectrum of epileptic disorders, d...

## Key facts

- **NIH application ID:** 10357918
- **Project number:** 5F31NS113530-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Chad R. Camp
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,238
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-02-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357918

## Citation

> US National Institutes of Health, RePORTER application 10357918, Loss of Grin2a Promotes Hippocampal Hyperexcitability and Epileptiform Activity (5F31NS113530-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10357918. Licensed CC0.

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