# Thalamocortical network dysfunction in a novel genetic model of GRIN2D developmental and epileptic encephalopathy

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $445,500

## Abstract

PROJECT SUMMARY
Developmental and epileptic encephalopathy (DEE) is a collection of severe childhood seizure disorders, with
a significant and diverse genetic component. DEE patients usually experience a significant seizure burden and
suffer from cognitive and developmental impairments, as well as sleep and motor disturbances. The 50 or
more genes harboring DEE-causing mutations include the “GRIN” genes, which encode components of
membrane protein complexes that are important for electrochemical signaling between neurons. Mutations in
the GRIN2D subunit cause particularly severe and intractable DEE. We recently developed a mouse model of
GRIN2D carrying a mutation that has recurred several times in GRIN2D DEE patients. These mice have very
robust epileptic features, including both convulsive seizures and non-convulsive seizures known to be
regulated by signaling between the cerebral cortex and the thalamus (i.e. thalamocortical network). This
thalamocortical network is also associated with regulation of sleep, awareness, and the activity of many other
brain regions. In preliminary findings, we also noticed that the protein product of Grin2D is expressed in
excitatory and inhibitory cells of the cortex, while it is enriched in the inhibitory cells of the thalamus.
Additionally, the primary sites of neuronal signaling – the synapse – have unusual structural features in the
cortex, suggesting that they do not develop normally. Altogether, these preliminary data motivate an
examination of how mutation in Grin2D alters the function of the cortex and thalamus. In this pilot program, we
will apply electrophysiological approaches to measure the function of synapses in the GRIN2D DEE model to
determine if structural changes correspond to functional impairments. We will also identify the neuronal
connections that are most severely affected within the thalamocortical network in GRIN2D DEE. Aim1 will use
slice electrophysiology methods to examine population-level responses within the cortex and thalamus to look
for susceptibility of these regions to generate seizure-like activity. We will also adapt innovative approaches to
dissect the component parts of the response in the cortex, which will allow us to efficiently pinpoint amongst
the many connections in the cortex, which are most likely altered by the Grin2D mutation. These network-level
effects will be further explored in Aim2 using intracellular whole-cell patch clamp recordings of synaptic
currents. Aim2 will assess two distinct modes of GRIN2D signaling, synaptic and tonic, which are associated
with different cellular consequences and are likely involved in the GRIN2D DEE pathogenic mechanism.
Together these experiments will determine the consequence of the GRIN2D DEE mutation on the activity of
neural circuits, which are implicated in the generation of seizures in these animals, and will determine, at the
cellular level, the underlying mechanism of epileptogenesis. This study is an important first st...

## Key facts

- **NIH application ID:** 10195508
- **Project number:** 1R21NS121980-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** WAYNE N. FRANKEL
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195508

## Citation

> US National Institutes of Health, RePORTER application 10195508, Thalamocortical network dysfunction in a novel genetic model of GRIN2D developmental and epileptic encephalopathy (1R21NS121980-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10195508. Licensed CC0.

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