Alternations of NMDA and GABAB Receptor Function in Development: a Potential Animal Model of Schizophrenia
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UNLV Theses, Dissertations, Professional Papers, and Capstones 8-1-2013 Alternations of NMDA and GABAB Receptor Function in Development: A Potential Animal Model of Schizophrenia Monica Bolton University of Nevada, Las Vegas Follow this and additional works at: https://digitalscholarship.unlv.edu/thesesdissertations Part of the Biology Commons, Medical Neurobiology Commons, Neuroscience and Neurobiology Commons, Neurosciences Commons, and the Psychology Commons Repository Citation Bolton, Monica, "Alternations of NMDA and GABAB Receptor Function in Development: A Potential Animal Model of Schizophrenia" (2013). UNLV Theses, Dissertations, Professional Papers, and Capstones. 1918. http://dx.doi.org/10.34917/4797986 This Thesis is protected by copyright and/or related rights. It has been brought to you by Digital Scholarship@UNLV with permission from the rights-holder(s). 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ALTERATIONS OF NMDA AND GABA B RECEPTOR FUNCTION IN DEVELOPMENT: A POTENTIAL ANIMAL MODEL OF SCHIZOPHRENIA by Monica Michelle Bolton Bachelor of Arts - Psychology Bachelor of Science - Biology University of Nevada, Las Vegas 2009 A thesis submitted in partial fulfillment of the requirement for the Master of Arts - Psychology Department of Psychology College of Liberal Arts The Graduate College University of Nevada, Las Vegas August 2013 Copyright by Monica Bolton, 2013 All Rights Reserved THE GRADUATE COLLEGE We recommend the thesis prepared under our supervision by Monica Bolton entitled Alternations of NMDA and GABA B Receptor Function in Development: A Potential Animal Model of Schizophrenia is approved in partial fulfillment of the requirements for the degree of Master of Arts - Psychology Department of Psychology Jefferson Kinney, Ph.D., Committee Chair Laurel Pritchard, Ph.D., Committee Member Joel Snyder, Ph.D., Committee Member Frank Van Breukelen, Ph.D., Graduate College Representative Kathryn Hausbeck Korgan, Ph.D., Interim Dean of the Graduate College August 2013 ii ABSTRACT Alterations of NMDA and GABAB Receptor Function in Development: A Potential Animal Model of Schizophrenia by Monica Bolton Dr. Jefferson Kinney, Examination Committee Chair Assistant Professor of Psychology University of Nevada, Las Vegas Schizophrenia is a debilitating mental disorder that affects up to 3% of the world population. The behavioral symptoms are categorized into positive and negative symptoms, which appear during late adolescence/early adulthood. Unfortunately, the underlying cellular and molecular mechanisms of the disease are poorly understood. Several hypotheses exist to explain mechanisms contributing to these behavioral alterations. One model proposes that a reduced function of the NMDA glutamate receptor on specific GABAergic interneurons may be responsible for deficits in schizophrenia. Post-mortem investigations provide evidence of reductions in both glutamate and GABA- related proteins in patients with schizophrenia. Further, GABAergic interneurons that are activated by glutamate via NMDA receptors are important for oscillatory activity involved with sensory processing and cognitive function. Alterations in the function of NMDA receptors on GABAeric interneurons are implicated in regulating neural network activity and, if disrupted, could potentially lead to altered brain function and deficits seen in schizophrenia. Several investigations have demonstrated reduction in NMDA receptor function or GABA receptor function induces deficits consistent with schizophrenia. Recent approaches have also focused on changes in NMDA or GABA function related to iii schizophrenia as a neurodevelopmental disorder. This approach suggests that alterations in either system during brain development may result in behavioral deficits later in life. The purpose of the below studies was to determine if changes in NMDA receptor function or alterations in downstream GABA receptor function during development in rodent pups results in behavioral or biochemical alterations in adulthood that are relevant to schizophrenia. The data reveal that altering these receptor systems in development produce deficits in adulthood. Changes in sensorimotor gating, spatial learning and memory, and differential expression of multiple GABA related proteins in the brain tissue were observed in these animals. iv TABLE OF CONTENTS ABSTRACT ....................................................................................................................... iii LIST OF FIGURES .......................................................................................................... vii CHAPTER 1 INTRODUCTION ........................................................................................ 1 CHAPTER 2 REVIEW OF RELATED LITERATURE .................................................... 5 Schizophrenia ...................................................................................................... 5 Glutamate Hypothesis of Schizophrenia ............................................................. 7 GABA Signaling ............................................................................................... 10 Neurodevelopmental Approaches ..................................................................... 20 Hypotheses and Implications ............................................................................ 27 CHAPTER 3 MATERIALS AND METHODS ............................................................... 30 Subjects ............................................................................................................. 30 Drug Treatments ................................................................................................ 30 Apparatus .......................................................................................................... 31 Prepulse Inhibition of Acoustic Startle ................................................. 31 Fear Conditioning Chambers ................................................................ 31 Morris Water Maze ............................................................................... 32 Tail Flick ............................................................................................... 32 Drug Administration ......................................................................................... 33 Behavioral Testing ............................................................................................ 33 Prepulse Inhibition of Acoustic Startle ................................................. 33 Cued and Contextual Fear Conditioning ............................................... 34 Morris Water Maze ............................................................................... 35 Tail Flick ............................................................................................... 36 Tissue Analysis ................................................................................................. 37 Tissue Collection ................................................................................... 37 SDS-PAGE Western Blotting ............................................................... 37 Statistical Analysis ............................................................................................ 39 CHAPTER 4 RESULTS ................................................................................................... 40 Behavioral Testing ............................................................................................ 40 Prepulse Inhibition of Acoustic Startle ................................................. 40 Cued and Contextual Fear Conditioning ............................................... 44 Morris Water Maze ............................................................................... 50 Tail Flick ............................................................................................... 55 Tissue Analysis ................................................................................................. 56 SDS-PAGE Western Blotting ............................................................... 56 v CHAPTER 5 DISCUSSION ............................................................................................. 62 REFERENCES ................................................................................................................. 79 VITA ............................................................................................................................... 103 vi LIST OF FIGURES Figure 1 Comparison of Rat and Human Brain Development ................................... 25 Figure 2 Acoustic Startle Responses.......................................................................... 41 Figure 3 Percent Prepulse Inhibition with 100 ms ISI ............................................... 42 Figure 4 Percent Prepulse Inhibition with 40 ms ISI ................................................. 43 Figure 5 Day 1 CCF Training .................................................................................... 44 Figure 6 Cued