# Mechanism and restoration of altered firing in interneurons during early phase Alzheimer's Disease

> **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $47,694

## Abstract

PROJECT SUMMARY
Alzheimer’s Disease (AD) is the most prevalent form of dementia, causing neuronal synapse (spine) loss, brain
atrophy, and eventual memory loss. Although AD is expected to grow from 5.8 million affected Americans to 13.8
million by 2050, there remains no effective preventative treatment. AD research has primarily focused on treating
pathological amyloid-beta plaques and tau tangles. However, recent research suggests plaque-and-tangle
pathology occurs relatively late in the disease. Recent studies in AD patients and models of disease have placed
hyperexcitability, increased pyramidal neuron firing, prior to amyloid-beta plaque pathology, providing an early
point for disease intervention. Pyramidal neuron hyperexcitability is a phenomenon that can result from an
imbalance of inhibitory/excitatory inputs. Recent literature has shown accordingly that distinct interneuron
subtypes are disrupted at this early disease state in mouse models, specifically fast-spiking parvalbumin (FS-
PV) interneurons. FS-PV interneurons display altered action potential firing in the prodromal phase of plaque
pathology in AD mouse models, resulting in pyramidal neuron hyperexcitability. It is known that firing patterns of
FS-PV interneurons can be altered through changes in the expression or biophysical properties of specific
voltage-gated channels (VGCs). This proposal seeks to determine 1. Mechanistic underpinnings of altered
FS-PV interneuron firing, and 2. If restored firing is successful in preventing pyramidal neuron
hyperexcitability and associated spine loss. In Aim 1, I predict altered FS-PV firing in pre-plaque AD is
caused by biophysical changes in VGCs. To assess these potential changes, I will use electrophysiological
methods to measure VGC biophysical changes. I will also isolate live FS-PV interneurons from wild-type and AD
mouse models to assess VGC mRNA expression changes. In Aim 2, I predict restored firing of FS-PV
interneurons in pre-plaque AD will prevent pyramidal neuron hyperexcitability and associated spine loss. In this
aim, restored firing of FS-PV interneurons will be achieved using two approaches: chemogenetics and a cell-
type-specific gene therapy. Pyramidal neuron hyperexcitability and morphology (spine loss) will be assessed
using patch-clamp electrophysiology and two-photon imaging. The results of this proposal will provide an early
point for AD intervention and a translatable therapeutic method with potential for neurodegeneration prevention.

## Key facts

- **NIH application ID:** 10710182
- **Project number:** 5F31AG076289-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Annie M Goettemoeller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10710182

## Citation

> US National Institutes of Health, RePORTER application 10710182, Mechanism and restoration of altered firing in interneurons during early phase Alzheimer's Disease (5F31AG076289-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10710182. Licensed CC0.

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