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Molecular Expression Analyses of Mice Treated with Antipsychotic Drugs

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Molecular Expression Analyses of Mice Treated with Antipsychotic Drugs Carlotta Elizabeth Duncan A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy The University of New South Wales January 2008 Supervisors: Professor Peter R. Schofield & Professor Cynthia Shannon Weickert ABSTRACT Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the population. The main treatments for schizophrenia are antipsychotic drugs that target dopamine receptors, yet the underlying biological mechanisms through which they alleviate the symptoms of schizophrenia remain ill defined. In this study, we used microarray analysis to profile the expression changes of thousands of genes simultaneously, following antipsychotic drug treatment of mice. Mice were treated chronically (28 days), or for a novel intermediate time-point (7 days), with one of three antipsychotic drugs: clozapine, haloperidol or olanzapine. The use of three drugs enabled us to discern antipsychotic-specific effects co-regulated by multiple drugs, rather than the side effects of individual compounds. Transcript profiling and validation by quantitative PCR of whole brain tissue revealed antipsychotic drug regulation of genes in diverse biological pathways, including: dopamine metabolism, neuropeptide and second-messenger signalling, neurogenesis, synaptic plasticity, cell adhesion, myelination, and voltage-gated ion channels. The regulation of voltage-gated channels by antipsychotic drugs has been suggested previously by electrophysiological studies, although thorough analysis has not been undertaken in vivo. Therefore, the second aim of this study was to characterise the regional mRNA and protein expression of two genes altered by multiple APDs, the voltage-gated potassium channel -subunit (Kcna1) and voltage- gated potassium channel interacting protein (Kchip3). Regional characterisation and expression analyses were carried out by immunohistochemistry, in situ hybridisation, and Western blot analysis of mouse brain regions of interest to schizophrenia and its treatment. Following 7-day haloperidol treatment we observed up-regulation of Kcna1 in the striatum and dentate gyrus, with increased protein in the striatum, hippocampus and midbrain; and down-regulation of Kchip3 in the striatum, with decreased protein in the cortex, hippocampus and midbrain. These studies implicate voltage-gated potassium channels in the antipsychotic drug regulation of midbrain dopaminergic neuronal activity, adult neurogenesis and/or striatothalamic GABAergic neuronal inhibition. These findings indicate that regulation of potassium channels may underlie some of the mechanisms of action of antipsychotic drugs, and that voltage-gated ion channels may provide alternative drug targets for the treatment of schizophrenia. i This thesis is dedicated to my Grandpa Mark: a prolific researcher, groundbreaking surgeon, lover of fine food and wine, and an inspiration to everyone whose life he touched. Mark B Coventry, M.D. 1913-1994 ii ACKNOWLEDGMENTS First and foremost I would like to thank my supervisor, Prof. Peter Schofield, who despite running an institute has been a rock when I needed one. Thank you for the opportunity to earn my PhD in two engaging environments. Dr. Carol Dobson- Stone provided a fantastically pedantic critical review of the thesis and some great early morning chats. My lab colleagues, past and present, from the Schofield lab: Dr Renee Morris, for mouse brain regional and protein expertise; Dr John Kwok, the Western and weather king!; Marianne – special thank you for your support throughout my PhD and your persistence with orders; Erica, thanks for lots of chocolate and yoga!; Dr Jan Fullerton, Dr Clement Loy, Kerrie, Anna and Mel, thank you for providing a lively work atmosphere. I’d also like to thank my present and future colleagues in the Schizophrenia Research Laboratory: Debora and Inara for keeping the lab running smoothly and for last minute desperate orders for me! Duncan and Cami for their assistance with experiments in the last year; Dr Sinthuja Sivagnanasundaram for reading my literature review; and also Dr Jenny Wong and Shan, thank you all for your help this year and I look forward to working with you next year. Profs Halliday and Garner, as well as members of their labs, particularly Dr Scott Kim, Elias, Heather and Karen, provided useful advice and resources and helped to ease the transition while settling into POWMRI. I’d also like to thank Prof. George Paxinos for his expertise in discerning regional expression patterns for in situ hybridisation and for use of his cryostat, for which Peter also provided invaluable technical advice. Additionally, Dr Warren Kaplan at the Garvan Institute bioinformatics department gave technical help with microarray data analysis and he and his staff were very patient with this non-statistician. An extra special thanks goes to (Dr) Agnes Luty, for suffering her PhD alongside me and providing inspiration and company during all those extra hours in the lab! Thanks must also be given to my family and friends. Mum and dad I could not have done this without your support – fiscal and emotional! I hope your pride in my achievements will one day parallel mine in yours. Dave, thanks for your support iii and understanding through this incredibly trying and exhausting year … you officially have your “comma-happy” girlfriend back! Andrew, you guided me into this field of interest, which I adore, and for that I am eternally grateful. I also enjoyed your retirement celebration and seeing the value and respect you have achieved in a lifetime in science, as my career is just beginning. James and Suzanne, your advice on my oral presentation skills was priceless, not to mention the wonderfully distracting conversations and dinners over the years…thank you! Liz and Gila, initially my colleagues in the lab and now eternal friends, I’m so proud of you both and look forward to the day when we can raise a cocktail to three “doctors”. There have been four women scientists who have inspired me to a life in science and trained me for this role: my high school chemistry teacher, Ms Oswald, and physics teacher, Dr Huxley, who humoured my adolescent angst and gave me an early love for science; my honours supervisor Prof. Emma Whitelaw who inspired me with her passion for epigenetics and encouraged me to remain in research; and Prof. Cyndi Shannon-Weickert – I am infinitely grateful for your supervising the final year of my PhD. Your breadth of knowledge is awe-inspiring and you have taught me so much about neuroscience, schizophrenia, the research world and commitment to a cause. I look forward to helping you cure schizophrenia. iv TABLE OF CONTENTS ABSTRACT……………………………………………………………………..i Acknowledgements…………………………………………………………..iii Table of contents………………………………………………………………v List of abbreviations and symbols……………………………………….xiii List of publications arising from this thesis…………………………….xv 1. INTRODUCTION.....................................................................1 1.1. Schizophrenia……………………………………………………....2 1.1.1. Classification……………………………………………………......2 1.1.1.1. History……………………………………………………...2 1.1.1.2. Onset and course…………………………………………...2 1.1.1.3. Clinical diagnosis.…………………………………………..3 1.1.1.4. Neurophysiological measures.……………………………...3 1.1.2. Neuropathology and imaging………………………………………4 1.1.2.1. Structural abnormalities……………………………………4 1.1.2.2. Cytoarchitectural abnormalities……………………………7 1.1.3. Proposed aetiological models………………………………………8 1.1.3.1. Neurodevelopmental hypothesis of schizophrenia………....8 1.1.3.2. Schizophrenia as a disorder of the synapse………………...9 1.1.4. Summary………………………………………………………….10 1.2. Neurochemistry and pharmacology in schizophrenia……..10 1.2.1. Neurotransmission occurs at the synapse…………………………10 1.2.2. History of neurochemistry and the treatment of schizophrenia…..11 1.2.2.1. Atypical versus conventional antipsychotic drugs………...13 1.2.3. The evolution of the dopamine hypothesis of schizophrenia……..15 1.2.3.1. Dopamine…………………………………………………15 1.2.3.2. Striatal dopamine hyperactivity underlies psychosis...……17 1.2.3.3. New support for dopamine hyperactivity in schizophrenia………………………………………………..18 1.2.3.4. A role for cortical dopamine hypoactivity………………...19 v 1.2.4. Glutamatergic dysfunction in schizophrenia……………………...21 1.2.4.1. Glutamate………………………………………………....21 1.2.4.2. NMDA receptor hypofunction in schizophrenia…………22 1.2.5. The present state of the field – a synthesis………………………..25 1.3. Molecular genetics of schizophrenia…………………………..27 1.3.1. Schizophrenia has a genetic predisposition……………………….27 1.3.2. Linkage and positional cloning……………………………………28 1.3.2.1. Neuregulin 1………………………………………………29 1.3.2.2. PPP3CC…………………………………………………..30 1.3.2.3. Dysbindin…………………………………………………31 1.3.2.4. G72/DAOA………………………………………………33 1.3.3. Cytogenetic abnormalities………………………………………...34 1.3.3.1. Microdeletions of 22q11…………………………………..34 1.3.3.2. DISC1 and partners………………………………………36 1.3.3.3. Other genes suggested through cytogenetic analysis……..37 1.3.4. Candidate genes and association studies………………………….38 1.3.4.1. COMT……………………………………………………38 1.3.4.2. ERBB4……………………………………………………40 1.3.4.3. GRM3…………………………………………………….41 1.3.4.4. BDNF……………………………………………………..41 1.3.4.5. GAD1…………………………………………………….42 1.3.4.6. RGS4……………………………………………………..42 1.3.4.7. AKT1……………………………………………………..43 1.3.5. Summary – schizophrenia susceptibility genes…………………...44 1.4. Gene expression profiling in schizophrenia………………….46 1.4.1. Techniques for
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