# Na+/Ca2+ exchanger remodeling in alcohol withdrawal seizures

> **NIH NIH R01** · HOWARD UNIVERSITY · 2023 · $347,625

## Abstract

Generalized tonic-clonic seizures (GTCSs), the most prevalent type of alcohol withdrawal‒induced seizures
(AWSs), are commonly resistant to current anticonvulsants, nevertheless, their underlying mechanisms are
poorly understood. Our long-term goal is to understand how altered Ca2+ signaling contributes to the neuronal
hyperexcitability that causes increased AWSs susceptibility. We have previously reported upregulation of
proteins associated to L-type (CaV1.3) and P-type (CaV2.1) voltage-gated Ca2+ (CaV) channels in inferior
colliculus (IC) neurons when AWSs prevalence peaks but not before the onset of AWSs susceptibility. The
upregulation of CaV channels leading to increased intracellular Ca2+ ([Ca2+]i) and altered Ca2+ homeostasis
suggests that the Na+/Ca2+ exchanger, a bidirectional membrane ion transporter that regulates [Ca2+]i would
preferentially operate in the forward mode (NCXfwd) to extrude Ca2+ and restore Ca2+ homeostasis. Surprisingly,
NCX operates in the reverse mode (NCXrev) causing Ca2+ influx into IC neurons prior to the onset of AWSs
susceptibility and when AWSs prevalence peaks. Thus, changes in NCX activity possibly play a critical role in
AWS initiation. The experiments proposed here will determine the precise contribution of NCX type1 (NCX1) to
neuronal hyperexcitability and AWSs susceptibility, providing specific target for developing novel therapeutics.
Our working hypothesis is that Ca2+ influx in IC neurons via NCXrev is essential for generating the epileptiform
bursts that initiate an AWS. To test this hypothesis—and building on our preliminary data and prior publications—
we will combine in vivo pharmacology with molecular genetics, electrophysiology, molecular biology, and
behavioral analysis in three specific aims. First, we will determine the extent to which NCXrev contributes to
generating the epileptiform bursts in IC neurons following alcohol withdrawal; in addition, we will investigate how
intracellular Na+ concentration as well as L- and P-type CaV channels contribute to increased NCXrev activity
during the course of alcohol withdrawal. Second, we will determine the extent to which changes in NCX1 gene
expression and cell surface protein levels in IC neurons are associated with increased seizure susceptibility
during the course of alcohol withdrawal. Third, we will evaluate AWSs generated in rats in which NCX1
expression is deleted selectively in IC neurons. Furthermore, we will measure AWSs in rats in which
hyperexcitability mediated by glutamatergic IC neurons is suppressed using optogenetics. Our findings will
provide key insight into NCX1 role on seizure activity, the mechanisms that initiate AWSs, and the mechanisms
that underlie AWSs and other types of GTCSs.

## Key facts

- **NIH application ID:** 10599223
- **Project number:** 5R01AA027660-05
- **Recipient organization:** HOWARD UNIVERSITY
- **Principal Investigator:** Prosper N'Gouemo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $347,625
- **Award type:** 5
- **Project period:** 2019-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599223

## Citation

> US National Institutes of Health, RePORTER application 10599223, Na+/Ca2+ exchanger remodeling in alcohol withdrawal seizures (5R01AA027660-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10599223. Licensed CC0.

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