# Plasticity of the entorhinal-hippocampal circuit as a vulnerability in AD

> **NIH NIH RF1** · BAYLOR COLLEGE OF MEDICINE · 2020 · $214,132

## Abstract

SUMMARY
Our study will test the hypothesis that the specific functional properties of entorhinal-hippocampal neurons may
contribute to their heightened vulnerability in AD. Our proposal is based on our preliminary data showing that neurons in
the entorhinal cortex (EC) are unusually sensitive to inactivity. Unlike neural populations affected in other
neurodegenerative diseases (including dopaminergic neurons in the substantial nigra, Purkinje neurons in the cerebellum,
and motor neurons in the spinal cord), EC neurons underwent cell death following even acute bouts of experimentally-
induced electrical arrest. Using a novel chemogenetic ion channel to prevent the firing of action potentials in EC layer 2
neurons, we found that entorhinal axons retracted from the dentate gyrus, followed by caspase activation at the cell body,
microglial activation in both areas, and finally, cell loss. This patterned degeneration in the adult brain mimics the
activity-dependent processes used in the developing brain to sculpt the perforant path (Yasuda et al., 2011). While it was
long believed that the critical period for wholesale structural remodeling closed during maturation, mounting evidence
indicates that some cortical areas maintain the potential for substantial modification throughout life. Based on our
findings, we hypothesize the ongoing plasticity required to support learning and memory throughout life also renders
neurons in the entorhinal-hippocampal circuit vulnerable to ongoing activity-dependent competition for survival in the
adult. We will test this hypothesis through three specific aims. Aim 1 will determine whether cell death arises from
competition between active and inactive cells or instead from inactivity itself. Restated, is cell death in EC neurons
initiated by a cell-autonomous or non-autonomous mechanism? This aim will also test whether other subfields of the tri-
synaptic loop with similar plasticity requirements are also dependent on continued electrical activity for survival in the
adult. Heightened plasticity in this circuit predicts that any initial impairments caused by EC cell loss will be quickly
offset by homeostatic compensation. Consistent with this idea, we find that young mice quickly regain normal learning
and memory performance after transient EC silencing despite ongoing cell death. Aim 2 will map the structural and
physiological reactions to loss of layer 2 neurons to identify changes in excitability or morphology that support circuit
repair. While the young adult brain can readily engage homeostatic mechanisms to compensate for circuit perturbation,
AD is a disease of aging when plasticity is more limited and the damage caused by insult more extensive. Aim 3 will test
whether a greater fraction of inactive neurons die in geriatric animals than in healthy young adults, and if the recovery of
perforant path transmission and hippocampal-dependent behaviors are slower and ultimately less successful. Collectively,
these aim...

## Key facts

- **NIH application ID:** 10078733
- **Project number:** 3RF1AG058188-01S2
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** JOANNA L JANKOWSKY
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $214,132
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078733

## Citation

> US National Institutes of Health, RePORTER application 10078733, Plasticity of the entorhinal-hippocampal circuit as a vulnerability in AD (3RF1AG058188-01S2). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10078733. Licensed CC0.

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