# Circadian changes in network excitability and Alzheimer disease pathogenesis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $720,765

## Abstract

PROJECT SUMMARY
 Converging evidence indicates that neuronal and network hyperexcitability is an important early event in
Alzheimer’s disease (AD) patients. The cellular and molecular basis of this hyperexcitability is a critical area of
investigation and the presence of similar hyperexcitability in animal models enables studies to dissect
underlying mechanisms. A key insight is that hyperexcitability in both AD patients and mouse models has a
strong diurnal rhythm. Emerging data also indicate that neural excitability in the forebrain is normally under
control of the circadian clock, which regulates seizure thresholds and susceptibility to epileptiform activity.
Circadian variation in cellular function is driven by transcriptional molecular clocks expressed in most cells, and
molecular clock ablation increases AD pathology. We have compelling preliminary evidence for rhythmic
variation in neuronal excitability that is at least partly due to circadian regulation of the membrane properties of
inhibitory interneurons, especially fast-spiking cells expressing parvalbumin (PV). Given that PV+ interneurons
in the cortex and dentate gyrus are strongly implicated in AD, and that circadian rhythms are disrupted in AD
patients and AD mouse models, we propose rigorous experiments to test the hypothesis that dysregulation of
the molecular clock and resulting changes in PV+ interneuron gene expression and activity contribute to AD-
related neuronal hyperexcitability. Specifically, we will evaluate the differences in circadian clock and clock-
controlled gene expression in PV+ interneurons vs. excitatory neurons in the mouse models of AD, using a
combination of RNA sequencing, state-of-the-art bioinformatics, and recently developed tools to evaluate
molecular clock rhythmicity and transcription in a cell-specific manner (Aim 1). We will record from inhibitory
and excitatory neurons in the dentate gyrus and cortex to determine if clock-driven changes in PV+ inhibitory
neuron activity are disrupted in AD models and contribute to overall hyperexcitability (Aim 2). Finally, we will
utilize an innovative chemogenetic chronotherapeutic approach to manipulate PV+ interneuron physiology to
determine whether reinstating the normal circadian patterns of PV+ interneuron activity in AD mice protects
against hyperexcitability, cognitive impairment, and pathology (Aim 3). The proposed studies led by a strong
interdisciplinary team use powerful approaches to determine how disruption of circadian rhythms facilitates
neuronal hyperexcitability that contributes to early stages of AD. Understanding these mechanisms may
catalyze development of behavioral or pharmacologic interventions.

## Key facts

- **NIH application ID:** 10486141
- **Project number:** 5R01AG061785-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Karen L Gamble
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $720,765
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486141

## Citation

> US National Institutes of Health, RePORTER application 10486141, Circadian changes in network excitability and Alzheimer disease pathogenesis (5R01AG061785-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10486141. Licensed CC0.

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