# GABA activation of the M-current

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $381,489

## Abstract

This Alzheimer’s disease (AD) supplement proposal is based on two recent discoveries from the Abbott lab.
The first discovery, which forms the basis of the parent R01, is that KCNQ2/3 voltage-gated potassium (Kv)
channels are directly activated by γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in
vertebrate CNS, with a sensitivity comparable to that of the most sensitive canonical GABAA receptors. This
newly described form of regulation is potentially highly influential because KCNQ2/3 channels are the primary
molecular correlate of neuronal M-current, a powerful inhibitory force in mammalian brain. The second
discovery is our more recent finding that the Alzheimer’s precursor protein (APP) cleavage product, C99, both
bears similarities to the KCNE family of Kv channel regulatory subunits, and itself regulates multiple Kv
channels, including those of the KCNQ family. Specifically, we found that C99 co-localizes with KCNQ2/3 in
vivo, forms physical complexes with KCNQ2/3 in vitro, and inhibits KCNQ2/3 function in vitro. We now intend to
study the relevance to AD of C99 regulation of KCNQ2/3 channels in vivo, as a logical extension of the parent
R01, bringing an AD perspective to it. We propose two Specific Aims directed towards a fuller understanding of
the novel potential role in AD pathology of C99, APP and potentially other APP cleavage product inhibition of
neuronal KCNQ channels. We plan to utilize the Kcnq3 and Kcnq5 GABA binding-site mutant mouse lines we
developed for the parent R01, in conjunction with the well-characterized 3xTg-AD mouse model that mimics
many features of human AD. In Aim 1, we will test the hypothesis that neuronal M-current is inhibited in the
3xTg-AD mouse brain. This hypothesis is based on our in vitro data, that suggest increased neuronal
concentrations of C99, and potentially other APP cleavage products, will inhibit neuronal M-current and alter its
gating kinetics in vivo. We will also determine whether 3xTg-AD mouse brains have altered GABA regulation of
M-current, linking this aim tightly with the parent R01 but with an AD focus that was absent from the parent
R01. In Aim 2, we will test the hypothesis that disrupted GABA regulation of M-current exacerbates behavioral
changes in AD. We will quantify behavioral changes in Kcnq3-W265L and Kcnq5-W270L GABA binding-site
mutant mice bred for the parent R01, in both a wild-type and 3xTg-AD background, and compare them to
homozygous 3xTg-AD mice, to determine if disruption of GABA modulation of KCNQ channels exacerbates AD
pathogenesis. The overall goals of this AD supplement are to (i) determine if C99 accumulation in early AD
correlates with downregulation of M-current, as suggested by our in vitro studies and (ii) determine how this
affects neuronal firing; (iii) identify whether preventing GABA modulation of KCNQ channels exacerbates
neuronal and M-current firing defects, and behavioral abnormalities, in AD. The studies in this supplement
have ...

## Key facts

- **NIH application ID:** 10119723
- **Project number:** 3R01NS107671-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Geoffrey W Abbott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,489
- **Award type:** 3
- **Project period:** 2020-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119723

## Citation

> US National Institutes of Health, RePORTER application 10119723, GABA activation of the M-current (3R01NS107671-02S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10119723. Licensed CC0.

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