# Excitability and Plasticity of Developing Epileptic Brain

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $429,766

## Abstract

Abstract
Our long term goal is to learn how an inherited single gene error produces a specific pattern of
epilepsy in the developing brain, to provide an exact description of relevant plasticity within
affected neural networks, and to reverse the seizure phenotype at the earliest possible stage.
Spike-wave (SW) absence seizures comprise a major category of inherited epilepsy in children,
and often herald cognitive deficits and more severe seizures. Over 20 mutant genes for this
phenotype are known, and their effects on channel behavior and routes of convergence on
excitability within thalamocortical pacemaking circuitry are now more clearly defined. The P/Q
calcium channel mouse mutant is a prototype for this analysis, and like other models, shows
elevated thalamic T-type calcium currents that are sufficient to generate absence epilepsy,
illuminating a shared downstream plasticity pathway triggered by functionally disparate
upstream SW genes. The mechanism underlying T-type current remodeling is not understood.
In the past project period we narrowed the critical pathogenic microcircuitry and found that
selective ablation of P/Q type calcium channels in Layer 6 corticothalamic neurons alone are
sufficient to elevate thalamic T currents and cause SW epilepsy, reducing the analysis from the
entire brain to a single thalamic afferent synapse, and showed that adult P/Q channel deletion
reproduces the childhood syndrome albeit through an alternative pattern of T current circuit
remodeling. Using newly created models, we will 1) analyze native and alternative thalamic
transcriptome changes to define the molecular basis for T current plasticity in thalamic
excitatory and inhibitory neurons and uncover novel epistatic genes participating in this switch,
2) test the thalamic current imbalance in a digenic model to simulate the combinatorial effects of
common human CAE variants in T currents, and 3) determine whether we can reverse the T
current imbalance and epileptic phenotype in PQ channel mutants by restoring normal PQ
function after the onset of seizures. This analysis brings us closer to molecular level treatments
of pathogenic gene expression in epilepsy.

## Key facts

- **NIH application ID:** 10435575
- **Project number:** 5R01NS029709-29
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jeffrey Noebels
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,766
- **Award type:** 5
- **Project period:** 1991-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435575

## Citation

> US National Institutes of Health, RePORTER application 10435575, Excitability and Plasticity of Developing Epileptic Brain (5R01NS029709-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10435575. Licensed CC0.

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