# Interneuron and Network Dysfunction in a Mouse Model of Alzheimer's Disease

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $43,920

## Abstract

Project Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive age-
related cognitive decline. Abnormal brain rhythms and interneuron dysfunction have been implicated in AD, but
it is unclear how these changes contribute to memory deficits. Studies linking specific network activity patterns
in specific circuits to memory decline will be needed in order to leverage new neurostimulation technologies to
normalize activity in these circuits and improve memory.
Interneurons play a critical role in synchronizing local networks to facilitate memory, but their contribution to
impaired hippocampal function in AD is not well understood. My lab has previously shown that proper timing of
hippocampal interneuron firing is disrupted in a mouse model of epilepsy, leading to desynchronized
communication in the hippocampal circuit. Hyperexcitability, seizures, and interneuron dysfunction have been
found in animal models of both epilepsy and AD, suggesting that cognitive dysfunction in these diseases may
share common mechanisms. In this proposal, I will test the hypothesis that the timing of hippocampal
interneuron firing relative to local oscillations is disrupted in 3xTg-AD mice and that these changes are
predictive of future memory impairments. I will use in vivo electrophysiology with silicon probes to record local
field potentials and single units throughout CA1, CA3, and dentate gyrus (DG) in head-fixed 3xTg and wild type
mice running in a virtual reality environment. Recordings and behavioral tests will be performed in the same
animals before and after the emergence of memory impairments. I hypothesize that interneurons in AD mice
will lose their temporal specificity relative to the phase of local oscillations, which will desynchronize
interneurons across the hippocampus. I further expect that extent of interneuron dysfunction will predict the
severity of future memory dysfunction.
In order to understand what network activity patterns are associated with improved cognition in AD, I will test
the hypothesis that the anti-epileptic drug Levetiracetam (LEV) improves memory by modifying hippocampal
network activity and interneuron function. This drug has been shown to normalize hyperexcitability and improve
memory in AD, but its precise mechanism is unknown. I will again perform silicon probe recordings in 3xTg and
WT mice to measure the acute and chronic impacts of LEV on the hippocampal circuit. I hypothesize that
chronic reduction of hyperexcitability by LEV will lead to improved synchrony in the hippocampus,
characterized by increased coherence and theta-gamma coupling, as well as increased temporal specificity of
interneuron firing. The results of these experiments will highlight specific cell populations and activity patterns
associated with memory dysfunction in AD and identify potential targets for early therapeutic interventions.

## Key facts

- **NIH application ID:** 10068307
- **Project number:** 1F31AG069496-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Lauren Vetere
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,920
- **Award type:** 1
- **Project period:** 2020-09-09 → 2023-09-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068307

## Citation

> US National Institutes of Health, RePORTER application 10068307, Interneuron and Network Dysfunction in a Mouse Model of Alzheimer's Disease (1F31AG069496-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068307. Licensed CC0.

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