# Circuit-based mechanisms of neuronal vulnerability in the adult EC

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2022 · $46,752

## Abstract

Project summary/abstract.
Entorhinal cortex layer II (ECII) neurons are some of the first cells to degenerate in Alzheimer’s Disease (AD). ECII
axons form the perforant pathway and are the major cortical input into the hippocampus. The perforant pathway supports
memory formation and spatial navigation throughout life, and loss of this input is consistent with the cognitive deficits
that present early in AD. To mimic the loss of this input in AD, the Jankowsky lab created a chemogenetic mouse model
of perforant pathway disruption in which a subset of ECII neurons express an engineered chloride channel (GlyCl) to
prevent the generation of action potentials. We unexpectedly discovered that entorhinal neurons were highly vulnerable to
silencing. Shortly after being inactivated, many ECII neurons retract their axons from the dentate gyrus, express pro-
apoptotic proteins, and then are eliminated from the circuit. We observed similar neurodegeneration after eliminating
neurotransmitter release with tetanus toxin (TeTX), confirming that neuronal loss is not an artifact of GlyCl activation.
Further, this silencing-induced degeneration is not shared by other brain regions, as neither the pre/parasubiculum nor
retrosplenial cortex exhibit cell loss after neuronal inactivation. This suggests that specific features of the entorhinal
cortex may confer neuronal vulnerability to inactivity. One possible vulnerability could be related to the formation of
entorhinal-hippocampal circuit. We noted that the pattern of ECII degeneration after silencing was strikingly similar to the
processes that guide to refinement of the perforant pathway during development. In early post-natal periods, inactive ECII
neurons are pruned from the circuit in a process that is mediated by local differences in activity, referred to as activity-
dependent competition. Projections are only pruned when neurons are sparsely inactive - when all cells are equally
inactive, none are removed. This proposal will test two hypotheses about the cellular mechanism driving neuronal death in
the mature entorhinal cortex. Aim 1 will determine whether activity-dependent competition persists in the adult ECII.
Pharmacological and genetic approaches will be used to modulate relative activity levels to determine how cell death is
influenced by activity differences between neighboring cells. Aim 2 will determine whether post-synaptic partners
promote the survival of ECII neurons. Our preliminary data suggests that eliminating neurotransmitter release from ECII
neurons – without blocking action potentials - is sufficient to induce degeneration. I will therefore use pharmacological
and genetic approaches to both reduce neurotransmitter binding in dentate granule cells and eliminate their ability to fire
action potentials in response to ECII input. This will test whether neurotransmitter-mediate signaling, or post-synaptic
activity itself, is required for ECII neuron survival. Data from these aims will determi...

## Key facts

- **NIH application ID:** 10400031
- **Project number:** 5F31AG067676-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Caleb Wood
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-04-15 → 2024-04-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400031

## Citation

> US National Institutes of Health, RePORTER application 10400031, Circuit-based mechanisms of neuronal vulnerability in the adult EC (5F31AG067676-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10400031. Licensed CC0.

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