# Mapping the Transcriptome of Age-Related Hippocampal Trisynaptic Circuit Dysfunction in a Rat Model for Alzheimer's Disease

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $206,250

## Abstract

Major barriers impede the translation of basic research findings from preclinical animal models of Alzheimer's
disease (AD) into the discovery of methods for early detection of AD onset and the treatment of memory
dysfunction. We hypothesize that early dysfunction of memory will be observable as dysfunction of
hippocampal trisynaptic circuit dynamics (TCDs) that are specifically associated with spatial memory. The
individual firing patterns of CA3 & CA1 pyramidal cells (or “place cells”) within the trisynaptic circuit can be
measured while acquisition, encoding, recall, and reconsolidation of spatial representations occurs. Our recent
in vivo studies of aged animals, a model for amnestic mild cognitive impairment, have revealed age and novelty
specific effects on CA3 & CA1 place cell dynamics that are rapidly reversed by acute administration of
levetiracetam + valproic acid (Robitsek 2015). We also hypothesize that changes in properties of single
neurons within the trisynaptic circuit will be an early signature for future behavioral impairment and for identifying
genome responses that may be most relevant to AD during the prodromal phase. In this multidisciplinary
application, we propose to use the novel TgF344-AD rat model (expressing mutant human amyloid precursor
protein (APPsw) and presenilin 1 (PS1ΔE9)) to identify hippocampal TCDs that change during development of
AD-associated memory dysfunction and to interrogate their underlying transcriptome and methylome. Prodromal
changes in neural activity appear to play a role in the progression of neuropathological changes observed in AD
by promoting the release of tau and the formation of neurofibrillary tangles. Accordingly, plasma tau levels are
associated with cognitive decline and conversion of mild cognitive impairment into dementia. Less is known,
however, about the cell specific response of the genome during the onset and course of AD progression that
may factor significantly into disease etiology and resilience, nor the composition of the transcriptome of individual
cells that respond dynamically to the onset and growing burden of inflammation. As a first step to fill this gap in
knowledge, we propose the following two Aims: 1) To determine the temporal window for altered neural
network activity in TgF344-AD rats that anticipates the age related progressive deterioration of spatial
memory (in vivo electrophysiology); and 2) To determine the transcriptome of unique cell types in the
TgF344-AD hippocampus (single cell RNA-sequencing (scRNA-seq) using a within-subjects design (Aim 1))
and the state of the TgF344-AD hippocampal genome as determined in parallel molecular studies (bulk
RNA-seq and Methyl-seq). The proposed research has the potential to detect prodromal signatures of genomic
events that underlie the onset of memory decline, uncovering relevant molecular determinants that may enable
interventions to enhance memory and, conceivably, slow disease progression and human suffering.

## Key facts

- **NIH application ID:** 9856957
- **Project number:** 5R21AG061553-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** David H Farb
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $206,250
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856957

## Citation

> US National Institutes of Health, RePORTER application 9856957, Mapping the Transcriptome of Age-Related Hippocampal Trisynaptic Circuit Dysfunction in a Rat Model for Alzheimer's Disease (5R21AG061553-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856957. Licensed CC0.

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