Mechanism and restoration of altered firing in interneurons during early phase Alzheimer's Disease

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PROJECT SUMMARY Alzheimer’s Disease (AD) is the most prevalent form of dementia, causing neuronal synapse (spine) loss, brain atrophy, and eventual memory loss. Although AD is expected to grow from 5.8 million affected Americans to 13.8 million by 2050, there remains no effective preventative treatment. AD research has primarily focused on treating pathological amyloid-beta plaques and tau tangles. However, recent research suggests plaque-and-tangle pathology occurs relatively late in the disease. Recent studies in AD patients and models of disease have placed hyperexcitability, increased pyramidal neuron firing, prior to amyloid-beta plaque pathology, providing an early point for disease intervention. Pyramidal neuron hyperexcitability is a phenomenon that can result from an imbalance of inhibitory/excitatory inputs. Recent literature has shown accordingly that distinct interneuron subtypes are disrupted at this early disease state in mouse models, specifically fast-spiking parvalbumin (FS- PV) interneurons. FS-PV interneurons display altered action potential firing in the prodromal phase of plaque pathology in AD mouse models, resulting in pyramidal neuron hyperexcitability. It is known that firing patterns of FS-PV interneurons can be altered through changes in the expression or biophysical properties of specific voltage-gated channels (VGCs). This proposal seeks to determine 1. Mechanistic underpinnings of altered FS-PV interneuron firing, and 2. If restored firing is successful in preventing pyramidal neuron hyperexcitability and associated spine loss. In Aim 1, I predict altered FS-PV firing in pre-plaque AD is caused by biophysical changes in VGCs. To assess these potential changes, I will use electrophysiological methods to measure VGC biophysical changes. I will also isolate live FS-PV interneurons from wild-type and AD mouse models to assess VGC mRNA expression changes. In Aim 2, I predict restored firing of FS-PV interneurons in pre-plaque AD will prevent pyramidal neuron hyperexcitability and associated spine loss. In this aim, restored firing of FS-PV interneurons will be achieved using two approaches: chemogenetics and a cell- type-specific gene therapy. Pyramidal neuron hyperexcitability and morphology (spine loss) will be assessed using patch-clamp electrophysiology and two-photon imaging. The results of this proposal will provide an early point for AD intervention and a translatable therapeutic method with potential for neurodegeneration prevention.