Semester

Spring

Date of Graduation

2014

Document Type

Thesis

Degree Type

MS

College

Eberly College of Arts and Sciences

Department

Psychology

Committee Chair

Miranda N. Reed

Committee Co-Chair

Melissa Blank

Committee Member

William Wonderlin.

Abstract

Individuals at risk for developing Alzheimer's disease (AD) often exhibit neuronal network hyperexcitability, particularly in the CA3 region of the hippocampus, in the years preceding AD diagnosis, suggesting that aberrant network activity might contribute to the pathogenesis of AD. Recently, the microtubule-binding protein tau has been implicated in this hyperexcitability. Removal of tau in AD models overexpressing amyloid-beta (Abeta) or non-AD models of epilepsy decreases hyperexcitability and normalizes the excitation/inhibition imbalance. The exact mechanism by which tau produces hyperexcitability remains to be determined, but recent work suggests tau may mediate glutamatergic signaling. Glutamate is the primary excitatory neurotransmitter in the central nervous system and changes in glutamatergic neurotransmission affect the overall activity of neuronal networks. Although beneficial at low levels, high concentrations of extracellular (EC) glutamate can lead to cell death through excessive activation of glutamate receptors, a process referred to as excitotoxicity and linked to several neurodegenerative disorders, including AD. Here, we used a tau mouse model of AD (rTg(TauP301L)4510) to examine whether mutant P301L tau expression alters synaptic glutamate regulation in the dentate gyrus (DG), CA3 and CA1 regions of the hippocampus. To examine glutamate regulation in vivo, we used an amperometry coupled to ceramic-based microelectrode arrays (MEAs), which allows for measurement of tonic glutamate levels, potassium-evoked glutamate release, and glutamate clearance from the synapse. P301L tau expression did not affect tonic extracellular glutamate levels or clearance from the synapse in any region examined. Similarly, amplitudes of potassium-evoked glutamate release were similar between controls and TauP301L mice in the DG and CA1. However, memory-impaired TauP301L mice exhibited a 7-fold increase in glutamate release in the CA3 region of the hippocampus, and spatial reference memory errors correlated with potassium-evoked glutamate release in the CA3. These data suggest a possible novel mechanism, increased presynaptic glutamate release, by which tau may mediate hyperexcitability.

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