# Determining mechanisms underlying hippocampal network disruption in early amyloid pathology: the role of PV basket cells on sharp wave ripples

> **NIH NIH F31** · GEORGETOWN UNIVERSITY · 2020 · $22,270

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease, characterized by learning and
memory deficits and the pathological accumulation of amyloid beta (Aβ) protein. Accounting for 60-70% of cases
of dementia, the disease has a rapidly expected increase in prevalence and cost to public health as world-wide
life expectancy increases. The cause of memory dysfunction in the disease is poorly understood however,
particularly at an early time-point of amyloid accumulation. In mouse models of AD, at ages preceding neuronal
or synaptic loss, there have been observed alterations in hippocampal sharp wave ripples (SWRs), neuronal
population events with a critical role in memory consolidation. The mechanisms underlying this disruption are
relatively unexplored however, a critical gap that the research proposed in this fellowship will examine. While it
is well-appreciated that amyloid accumulation impairs the synaptic function of excitatory pyramidal cells (PCs),
there is growing evidence that inhibitory GABAergic cells are also compromised. Amyloid accumulation has been
shown to disrupt the activity of parvalbumin (PV) expressing inhibitory basket cells (PVBCs), cells which have a
critical role in regulating SWR events. PV cells are unique in that they are the major neuronal subtype ensheathed
in peri-neuronal nets (PNNs), part of the extracellular matrix of proteins that regulate and support cellular activity.
This proposal will explore if a preferential amyloid-induced disruption to PVBCs and the PNNs that surround
them can account for alterations to SWR events. Parallel biochemical and electrophysiological studies will seek
to determine if reduced excitatory input to this cell type results in decreased inhibitory drive to the hippocampal
network, potentially causing the hyperexcitable activity often observed in early amyloid pathology. This
mechanism will be further explored by monitoring the activity of excitatory PCs, both through patch clamp
electrophysiology and calcium imaging to record ensemble dynamics. A biophysical computational model will
determine if the proposed PVBC-PC mechanism is sufficient to explain observed SWR and ensemble disruption.
The training proposed in the advanced techniques of whole-cell biocytin-injection and computational modeling
will facilitate the determination of the neuronal mechanisms underlying hippocampal network disruption in early
amyloid pathology. As this activity is critical for memory consolidation, these findings will provide a therapeutic
target to potentially ameliorate memory decline.

## Key facts

- **NIH application ID:** 9940671
- **Project number:** 5F31AG062030-02
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Adam Caccavano
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $22,270
- **Award type:** 5
- **Project period:** 2019-05-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940671

## Citation

> US National Institutes of Health, RePORTER application 9940671, Determining mechanisms underlying hippocampal network disruption in early amyloid pathology: the role of PV basket cells on sharp wave ripples (5F31AG062030-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9940671. Licensed CC0.

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