Date of Completion

6-10-2015

Embargo Period

12-7-2015

Keywords

Parvalbumin, Ketamine, Schizophrenia, Age, Cognition, Spatial Memory, Radial Water Maze

Major Advisor

James J. Chrobak

Associate Advisor

Chi-Ming Chen

Associate Advisor

John D. Salamone

Associate Advisor

R. Holly Fitch

Associate Advisor

Etan Markus

Field of Study

Psychology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

A marked and selective decrease in the overall expression of the calcium-binding protein, parvalbumin (PV), has been a consistent postmortem finding in patients with schizophrenia. The documented reduction in calcium-binding protein immunoreactivity is specific to PV, and is observed exclusively within the prefrontal cortex and hippocampus (HPC) of patients. Models of schizophreniform cognitive dysfunction induced by chronic NMDA-receptor hypofunction utilizing non-competitive NMDA antagonist drugs such as ketamine (KET), have been shown to show comparable decreases in HPC and prefrontal cortical PV expression. Down-regulation of PV immunoreactivity within these key brain regions associated with cognition is often considered to be a marker for underlying neural pathology. However, contradictory findings are present in the literature, with some groups reporting decreased, increased, or no change in PV expression following comparable NMDA antagonist treatments. Upon examining methodology across studies, it is clear that inconsistencies, particularly with regard to the age of subjects, time of tissue collection, and treatment-induced behavioral impairments as related to PV outcomes. In order to better understand the distinct roles of these factors on PV expression, the present set of studies within this dissertation sought to elucidate upon the following: 1) age-dependent baseline regulation of PV expression; 2) effect of chronic KET treatment (30 mg/kg IP; 14 consecutive days) on cognitive performance in a spatial memory task; 3) effect of chronic KET treatment on PV expression, and its relationship to observed cognitive impairment; and 4) the interaction between age and KET administration on PV expression. The findings presented herein provide evidence suggesting a dynamic interaction between age and chronic KET treatment on overall PV expression within HPC and neocortical regions. Based on our data, we propose that PV expression is a highly dynamic neuronal marker, which can be modulated based on a myriad of factors (e.g. age, experience, treatment, etc.). Taken together, the findings from the present work suggest that changes in PV expression following NMDA antagonist treatment should be considered in the context of age, and that PV may not be an accurate or translational marker of pathological dysfunction.

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