All ETDs from UAB

Advisory Committee Chair

Erik D Roberson

Advisory Committee Members

Rita M Cowell

Linda O Wadiche

J David Sweatt

John J Hablitz

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The incidence of Alzheimer's disease (AD) is increasing with the aging population and an astonishing 5.2 million Americans are affected by AD, the most common cause of dementia. Cognitive impairment worsens with declining hippocampal function. Neuronal hyperexcitability occurs early in the pathogenesis of AD and contributes to network imbalance and the seizure activity seen in AD patients. In other disorders with neuronal hyperexcitability, dysfunction in the dendrites often contributes, but dendritic excitability has not been studied in AD models. We used patch-clamp recordings to directly examine dendritic excitability in the CA1 region of the hippocampus. We found that dendrites, but not the soma of hippocampal neurons, were hyperexcitable in the hippocampus of mice overexpressing human APP/Aß. This dendritic hyperexcitability was associated with depletion of Kv4.2, a dendritically-localized potassium channel important in the regulation of dendritic excitability, synaptic plasticity, and learning and memory. We found that epileptiform activity drives the reduction in Kv4.2, and blocking epileptiform activity by tau reduction prevented both Kv4.2 depletion and dendritic hyperexcitability. The dendritic hyperexcitability induced by Kv4.2 depletion exacerbates behavioral deficits induced by Aß and further increases dendritic excitability, creating a detrimental feedback loop. Therefore, we conclude that Kv4.2 is a dendritic effector downstream of Aß and that increased dendritic excitability may contribute to neuronal dysfunction in early stages AD.

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