Assessing Neuronal Vulnerability in the Entorhinal Cortex due to Alzheimer's Disease Pathology

PROJECT SUMMARY Understanding how specific neurons in a selectively vulnerable region such as the EC are affected is critical to unraveling the mechanisms underlying Alzheimer's disease onset. We and others have shown that neuronal hyperexcitability is the key driver that makes pathologies and symptoms worse and ameliorating hyperexcitability slows down AD-related symptoms. However, it is unclear if the hyperexcitability is due to an increased firing of excitatory neurons or decreased firing of inhibitory neurons. We aim to understand the mechanisms underlying hyperexcitability by studying the excitatory and inhibitory neurons in the EC of App and tau knockin mice. To determine which type of neurons are affected early in the EC, we will investigate: Aim 1- Excitatory neurons in the App knockin (AppNL-G-F) and tau knockin (hTau-KI) mice by using intersectional approach with optogenetics and chemogenetics in combination with electrophysiology recordings and behavior and Aim 2- Inhibitory neurons (parvalbumin- PV and somatostatin- SST) in the AppNL-G-F and hTau-KI mice as in aim 1. Using Cre-specific mice to target excitatory and inhibitory neurons in combination with opto- or chemo- genetic approach we will not only identify selectively vulnerable neuron-type, but we will also modulate their activities to restore their function and test if behavioral deficits are reversed. We will use novel computational approaches such as decoding and remapping to detect subtle changes in firing activity of EC neurons. We will also assess how amyloid beta or tau affect different neuron types in the EC, and if downstream hippocampal neurons are affected too. The results of the proposal will definitively answer if hyperexcitability of neurons due to AD pathologies is caused by dysfunction of excitatory or inhibitory neurons. The sensitive computational methods used in this proposal allow for measurement of subtle electrophysiological changes not possible previously and therefore might allow for development of better diagnostic tests that could be translated and modified for clinical use in humans. Overall, the proposal aims to identify which neurons in the MEC are most vulnerable to AD pathology. The proposal is highly innovative as it will use a combination of sophisticated in vivo recording in two AD mouse models in combination with optogenetic and chemogenetic tools to identify specific cell type and modulate neuronal firing to restore function. The results from the study will be highly significant as therapeutic or clinical approaches to target vulnerable cell type could be identified. The proposal brings together diverse fields (electrophysiology, pathology and computational neuroscience) applying large-scale recording techniques to record ensemble populations of neurons to interrogate what causes hyperexcitability in a vulnerable brain region that is dysfunctional in Alzheimer’s disease.