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Identification of Novel Candidate Genes Involved in Individual Antidepressant Treatment Response

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Identification of Novel Candidate Genes Involved in Individual Antidepressant Treatment Response Identification of novel candidate genes involved in individual antidepressant treatment response Dissertation an der Fakultät für Biologie der Ludwig-Maximilians-Universität München Vorgelegt von Christiana Labermaier München, September 2014 Dissertation eingereicht am: 18.09.2014 Mündliche Prüfung am: 06.02.2015 1. Gutachter: PD Dr. Mathias V. Schmidt 2. Gutachter: Prof. Dr. Benedikt Grothe 3. Gutachter: Prof. Dr. Gisela Grupe 4. Gutachter: Prof. Dr. Angelika Böttger 5. Gutachter: PD. Dr. Mario Wullimann 6. Gutachter: PD. Dr. Martin Heß „Wenn du ein Schiff bauen willst, dann trommle nicht Männer zusammen, um Holz zu beschaffen und Arbeit einzuteilen, sondern lehre die Männer die Sehnsucht nach dem weiten endlosen Meer!“ Antoine de Saint-Exupéry (1900 -1944) ___________________________________________________________TABLE OF CONTENTS Table of Contents Table of Contents .................................................................................................... I List of Abbreviations ............................................................................................... V Abstract .................................................................................................................. X Zusammenfassung ................................................................................................ XI 1 Introduction ...................................................................................................... 1 1.1 Depression ......................................................................................................................... 1 1.2 Antidepressant drugs ......................................................................................................... 6 1.3 Depression and the hippocampus ...................................................................................... 9 1.4 Gene expression profiling in depression .......................................................................... 11 1.5 SRY-box containing gene 11 (Sox11) - a novel antidepressant-inducible gene .............. 13 1.6 Animal model of depression ............................................................................................. 14 1.7 Aim of the thesis ............................................................................................................... 17 2 Materials and Methods................................................................................... 18 2.1 Animals ............................................................................................................................. 18 2.2 Experimental design ......................................................................................................... 18 2.2.1 Validation of a novel approach to investigate antidepressant response in mice...... 18 2.2.1.1 Paroxetine - Dosage ................................................................................................. 18 2.2.1.2 Paroxetine - Acute treatment effects ........................................................................ 19 2.2.1.3 Route of administration: Acute administration of mouse pellets versus intraperitoneal injection (i.p.) ............................................................................................................ 20 2.2.1.4 Pharmacokinetics of paroxetine ............................................................................... 20 2.2.1.5 The Forced Swim Test as a readout parameter for antidepressant response ......... 21 2.2.2 Detection of potential novel candidate genes after chronic paroxetine treatment ... 22 2.2.3 The role of Sox11 in antidepressant response and depression ............................... 23 2.2.3.1 Characterization of Sox11 under different treatment conditions .............................. 23 2.2.3.2 The effects of reboxetine on Sox11 expression ....................................................... 23 2.2.3.3 Sox11 OE and its influence on neurogenesis .......................................................... 24 2.2.3.4 Sox11 knockdown in combination with paroxetine treatment and its influence on antidepressant-like behavior .................................................................................... 25 I TABLE OF CONTENTS _________________________________________________________ 2.2.4 Detection of potential novel candidates after subchronic paroxetine treatment in the brain and periphery ................................................................................................... 25 2.3 Antidepressant treatment ................................................................................................. 26 2.4 Sampling procedure ......................................................................................................... 27 2.5 Modeling antidepressant response in mice with the FST................................................. 28 2.6 Behavioral testing ............................................................................................................. 29 2.6.1 Open field test .......................................................................................................... 29 2.6.2 Dark-light box ........................................................................................................... 30 2.6.3 Novelty induced hypophagia .................................................................................... 30 2.6.4 Y-Maze ..................................................................................................................... 31 2.6.5 The Forced Swim Test ............................................................................................. 31 2.7 Molecular methods ........................................................................................................... 31 2.7.1 Radioimmunoassay .................................................................................................. 31 2.7.2 Paroxetine concentrations in the brain and plasma ................................................. 32 2.7.3 RNA isolation ............................................................................................................ 32 2.7.3.1 Whole blood .............................................................................................................. 32 2.7.3.2 Whole blood RNA globin reduction .......................................................................... 33 2.7.3.3 Hippocampus ............................................................................................................ 33 2.7.4 RNA amplification ..................................................................................................... 33 2.7.5 cDNA transcription .................................................................................................... 34 2.7.6 Microarray analysis ................................................................................................... 34 2.7.7 Quantitative reverse transcription PCR .................................................................... 34 2.7.8 In situ hybridization ................................................................................................... 37 2.7.9 Immunohistochemistry and immunostaining ............................................................ 38 2.8 Stereotactic surgery.......................................................................................................... 38 2.8.1 Viral vector construct ................................................................................................ 38 2.8.2 Stereotactic intra-hippocampal injection ................................................................... 38 2.9 Statistics ........................................................................................................................... 39 3 Results ........................................................................................................... 40 3.1 Antidepressant response in mice - methodological considerations ................................. 40 3.1.1 Dosing....................................................................................................................... 40 3.1.2 Acute antidepressant administration ........................................................................ 44 3.1.3 Acute i.p. injection versus acute mouse pellet ......................................................... 46 3.1.4 Half-life study ............................................................................................................ 47 II TABLE OF CONTENTS 3.1.5 The FST as a valid readout for antidepressant treatment outcome in mice ............ 48 3.2 Genes and pathways modulated after chronic paroxetine treatment ............................... 49 3.2.1 Microarray analysis ................................................................................................... 49 3.2.2 Validation of potential candidates with qRT-PCR .................................................... 51 3.3 Sox11 as a potential novel candidate mediating antidepressant action .......................... 54 3.3.1 Chronic paroxetine treatment leads to a robust upregulation of Sox11 ................... 54 3.3.2 Subchronic paroxetine treatment leads to higher Sox11 mRNA expression ........... 55 3.3.3 Acute paroxetine treatment does not alter Sox11 gene expression ........................ 55 3.3.4 Sox11 upregulation is a SSRI specific effect............................................................ 56 3.3.5 Viral overexpression of Sox11 leads to a less anxious phenotype .........................
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