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.
Recommended Citation
Hall, Alicia Marie, "Contribution of Kv4.2 to Neuronal Hyperexcitability in a Mouse Model of Alzheimer's Disease" (2014). All ETDs from UAB. 1844.
https://digitalcommons.library.uab.edu/etd-collection/1844
