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Identifying the Mechanisms of Antidepressant Drug Action in Mice Lacking Brain Serotonin

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Identifying the Mechanisms of Antidepressant Drug Action in Mice Lacking Brain Serotonin Identifying the mechanisms of antidepressant drug action in mice lacking brain serotonin D I S S E R T A T I O N zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin von Markus Petermann Präsidentin der Humboldt-Universität zu Berlin Prof. Dr.-Ing. Dr. Sabine Kunst Dekan der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin Prof. Dr. Bernhard Grimm Gutachter 1. Prof. Dr. Michael Bader 2. Prof. Dr. Rüdiger Krahe 3. Prof. Dr. Golo Kronenberg Tag der mündlichen Prüfung: 08. Januar 2021 https://doi.org/10.18452/23035 EIDESSTATTLICHE ERKLÄRUNG ZUR SELBSTSTÄNDIGKEIT 2 SUMMARY 3 ZUSAMMENFASSUNG 4 1 INTRODUCTION 5 1.1 MAJOR DEPRESSIVE DISORDER 5 DEFINITION AND HISTORICAL DEVELOPMENT 5 HYPOTHESIS OF DEPRESSION 8 1.2 MONOAMINE HYPOTHESIS OF DEPRESSION 9 THE MONOAMINE SEROTONIN AND ITS HISTORICAL RELEVANCE 9 SEROTONIN BIOSYNTHESIS AND METABOLISM 9 PERIPHERAL SEROTONIN 11 THE NEUROTRANSMITTER SEROTONIN 12 NEUROANATOMY OF THE SEROTONIN SYSTEM IN MOUSE AND HUMAN BRAIN 13 SEROTONIN-RECEPTORS 14 SEROTONIN TRANSPORTER 15 ADULT NEUROGENESIS 18 SEROTONIN AS THERAPEUTIC TARGET 20 SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI) 22 SELECTIVE SEROTONIN REUPTAKE ENHANCER (SSRE) 23 ELECTROCONVULSIVE THERAPY 24 1.3 ANIMAL MODELS AS A TOOL FOR RESEARCHING THE SEROTONIN SYSTEM 26 TPH2 - DEFICIENT MICE 26 SERT - DEFICIENT MICE 29 1.4 NEUROTROPHIN HYPOTHESIS OF DEPRESSION 30 THE NEUROTROPHINS AND BDNF 30 BDNF BIOSYNTHESIS AND PATHWAYS 30 ALTERED BDNF SIGNALING IN DISEASE – ANTIDEPRESSANT EFFECTS OF BDNF 32 1.5 NEURO-ENDOCRINE SYMPTOM OF DEPRESSION AND THE STRESS HYPOTHESIS 33 PHYSIOLOGICAL STRESS 33 DYSREGULATION OF THE HPA-AXIS AND THE STRESS RECEPTORS 34 1.6 BIOMARKERS FOR DEPRESSION 36 1.7 AIMS 38 COMPARISON OF THE PHYSIOLOGICAL EFFECTS MEDIATED BY SSRI AND SSRE TREATMENT 38 TEST ELECTROCONVULSIVE THERAPY (ECT) IN A MODEL WITH SEROTONIN DEPLETION 38 ELUCIDATING THE ROLE OF SEROTONIN ON THE HPA-AXIS 38 ALTERATIONS IN DAILY LIFE ACTIVITIES AS A BEHAVIOR BIOMARKER FOR DEPRESSION 39 2 METHODS 40 2.1 ANIMALS AND HOUSING CONDITIONS 40 TPH2-/- 40 SERT-/- 40 ACE2-/- 40 HOUSING CONDITIONS 40 2.2 BRDU AND DRUG TREATMENT 41 BRDU TREATMENT 41 SSRI, SSRE TREATMENT 41 2.3 EXPERIMENTAL DESIGNS 42 COMPARISON OF THE PHYSIOLOGICAL EFFECTS MEDIATED BY SSRI AND SSRE TREATMENT 42 TEST ELECTROCONVULSIVE THERAPY (ECT) IN A MODEL WITH SEROTONIN DEPLETION 42 ELUCIDATING THE ROLE OF SEROTONIN ON THE HPA-AXIS 43 ALTERATIONS IN DAILY LIFE ACTIVITIES AS A BEHAVIOR BIOMARKER FOR DEPRESSION 44 2.4 GENOTYPING 44 GDNA ISOLATION 44 PCR-AMPLIFICATION OF THE TEMPLATE DNA 45 GEL ELECTROPHORESIS FOR DNA SEPARATION 46 2.5 TISSUE PREPARATION 46 ANESTHESIA OF ANIMALS 46 ANIMAL PERFUSION 47 ORGAN SECTIONING AND CRYOPROTECTION 47 TRUNK BLOOD COLLECTION AND PLASMA ISOLATION 47 2.6 HISTOLOGY / IMMUNOFLUORESCENCE 48 DAB-LABELING OF BRDU-POSITIVE CELLS 48 IMMUNOFLUORESCENCE OF BRDU-POSITIVE CELLS FOR PHENOTYPIC ANALYSIS 49 QUANTIFICATION OF CELL PROLIFERATION AND SURVIVAL 50 TUNNEL CELL DEATH STAINING 50 2.7 ELISA 51 STANDARD CURVE CALCULATION FOR ENDOCRINE HPA-PARAMETERS 51 BDNF 51 CORT / GLUCOCORTICOIDS 51 ACTH 52 2.8 QPCR FOR MRNA EXPRESSION OF HPA-AXIS PARAMETERS 52 COMPLEMENTARY DNA (FIRST STRAND) SYNTHESIS 52 QUANTITATIVE REAL-TIME PCR (QRT-PCR / QPCR) 53 SPECTROMETRIC MEASUREMENT OF NUCLEIC ACID CONCENTRATION 54 2.9 BEHAVIORAL TESTING 55 ELEVATED O-MAZE 55 OPEN FIELD 55 FORCED SWIM TEST 56 NESTING BEHAVIOR 56 HOARDING 57 BURROWING 58 2.10 VAGINAL SMEAR ANALYSIS TO DETERMINE ESTRUS CYCLE STAGES 58 2.11 STATISTICAL ANALYSIS 59 2.12 MISCELLANEOUS SOFTWARE 60 3 RESULTS 61 3.1 COMPARISON OF THE PHYSIOLOGICAL EFFECTS MEDIATED BY SSRI VS. SSRE TREATMENT 61 THE EFFECTS OF THE SSRI CIT ON ADULT NEUROGENESIS IN TPH2-/- MICE AND CONTROL 61 CELL SURVIVAL W/O TREATMENT 62 THE EFFECTS OF THE SSRE TIA ON ADULT NEUROGENESIS IN TPH2-/- MICE AND CONTROL 63 PHENOTYPIC ANALYSIS AND APOPTOSIS 65 3.1.5 CIT TREATMENT DECREASES BDNF PROTEIN LEVELS IN TPH2-/- MICE 69 3.2 DYSREGULATION OF THE HPA-AXIS IN THE ABSENCE OF SEROTONIN 71 CORT AND ACTH PLASMA LEVELS 71 CORT AND ACTH LEVELS UPON TREATMENT PARADIGMS 75 CRF AND POMC LEVELS IN HYPOTHALAMUS 77 NO INFLUENCE OF ESTROUS CYCLE ON CORT AND ACTH LEVELS 80 OPEN FIELD TEST UPON TREATMENT 81 GLUCOCORTICOID-, AND MINERALOCORTICOID RECEPTOR GENE EXPRESSION 83 3.3 ELECTROCONVULSIVE SEIZURE (ECS) 92 ECS DOES NOT AFFECT ANXIETY LEVELS BUT ATTENUATES THE HIGHLY ACTIVE PHENOTYPE OF TPH2-/- MICE 92 REDUCED NEUROBIOLOGICAL RESPONSES TO ECS IN TPH2-/- MICE 95 3.4 BEHAVIORAL SETUPS AS A BIOMARKER FOR DEPRESSION 97 REDUCED NESTING BEHAVIOR IN THE LACK OF SEROTONIN 97 HOARDING AND BURROWING 99 4 DISCUSSION 101 4.1 MONOAMINE HYPOTHESIS – SEROTONIN IS TARGET IN SSRI BUT NOT SSRE FUNCTION 101 STRESS EFFECTS ON ADULT NEUROGENESIS 104 THE SSRE TIA – A DOUBTFUL “HYPOTHESIS-KILLER” ! 106 4.2 NEUROTROPHIN HYPOTHESIS – BDNF IS INVOLVED IN BRAIN PLASTICITY IN THE ABSENCE OF SEROTONIN 108 4.3 SEROTONIN AFFECTS THE HPA-AXIS 111 RECEPTORS OF THE STRESS AXIS 114 SEX-SPECIFIC PHYSIOLOGICAL FUNCTIONS OF SEROTONIN 117 SERT−/− MICE ARE PERFECT COUNTERPARTS FOR THE STRESS-RESULT FROM TPH2-/- MICE 119 4.4 ELECTROCONVULSIVE THERAPY (ECT) IN A MODEL WITH SEROTONIN DEPLETION 121 4.5 BEHAVIOR AS BIOMARKER 124 4.6 CONCLUSION 126 5 MATERIAL 128 5.1 ANTIBODIES 130 5.2 OLIGONUCLEOTIDES (PRIMERS) 130 5.3 LABORATORY EQUIPMENT 132 5.4 SOFTWARE 133 6 ABBREVIATIONS 134 7 BIBLIOGRAPHY 137 8 LIST OF TABLES 160 9 TABLE OF FIGURES 162 Dedicated to Sven, Rike & Theresa 1 Eidesstattliche Erklärung zur Selbstständigkeit Eidesstattliche Erklärung zur Selbstständigkeit Hiermit erkläre ich, dass ich die vorliegende Arbeit selbstständig und nur unter der Verwendung der angegebenen Quellen und Hilfsmittel angefertigt habe. Alle Materialien oder Dienstleistungen, die ich von Dritten erhalten habe, sind als solche gekennzeichnet. Ich versichere, dass ich mich nicht anderswertig um einen Doktorgrad beworben habe oder einen entsprechenden Doktortitel bereits besitze. Die Promotionsordnung der Lebenswissenschaftlichen Fakultät (Stand 5. März 2015) der Humboldt-Universität zu Berlin ist mir bekannt. __________________________ Markus Petermann Berlin; 01. September 2020 2 Summary Summary Serotonin is well-known as the "molecule of happiness" and the most important target for antidepressants. The mainly prescribed drugs in major depression are selective serotonin re-uptake inhibitors (SSRI); but recently, SSR-enhancer (SSRE) have also attracted clinical attention. However, only a quarter of patients responds to treatment and research into the drug mechanisms revives. It needs to be determined, whether SSRI/E act solely via manipulating serotonin levels or whether other pathways are involved, e.g. neurotrophic signaling (brain-derived neurotrophic factor, BDNF) or the hypothalamus-pituitary-adrenal (HPA)-axis. Furthermore, in major depression, dysregulation of central serotonin signaling is accompanied with a decline in hippocampal neurogenesis, as has been observed in rodent models. Therefore, to elucidate the interplay of serotonin, BDNF, adult neurogenesis and the HPA-axis is of importance. At the center of this thesis is a mouse model deficient in the central serotonin- synthesizing enzyme, tryptophan hydroxylase 2 (Tph2-/- mice). Using molecular biology tools, treatment, and behavioral paradigms, I have investigated physiological responses to antidepressant treatment in the absence of brain serotonin, and the possible role of alternative pathways. I observed the typical increase in neurogenesis upon SSRI treatment in WT mice, while it had no effect in Tph2-/- mice. In contrast, BDNF levels were significantly decreased in Tph2-/- mice after treatment with no effect in WT control mice. Furthermore, my results show a critical role of brain serotonin in the neurobiological effects of electroconvulsive seizure. Surprisingly, in animals lacking central serotonin, increased neurogenesis was observed independently of the treatment. The gathered data indicated an altered stress response; therefore, parameters of the HPA-Axis have been studied, indicating a downregulated HPA system in Tph2-/- animals in baseline state, but showed no difference in treatment or feedback control. This thesis gives insight into the mechanisms of antidepressant action and reveals ideas for novel pathways involved in the process that could be used as targets in therapeutic approaches and further research in major depression. 3 Zusammenfassung Zusammenfassung Serotonin ist bekannt als das "Glückshormon" und gilt als Hauptangriffsstelle der heute gängigsten Antidepressiva. Die am häufigsten verschriebenen Medikamente bei schweren Depressionen sind selektive Serotonin-Wiederaufnahmehemmer (SSRI). Dennoch erzeugten aufgrund guter Verträglichkeit im letzten Jahrzehnt aber auch SSR-Enhancer (SSRE) klinische Aufmerksamkeit. Nur etwa ein Viertel der Patienten sprechen auf therapeutische antidepressive Behandlungen an, weswegen eine große Notwendigkeit des Verständnisses ihrer Wirkungsweisen besteht. Es bleibt offen, ob SSRI / E ausschließlich über die Manipulation des Serotoninspiegels wirken, oder ob alternative Signalwege daran beteiligt sind. Ansatzpunkte hierfür sind beispielsweise die neurotrophen Signalwege (besonders Brain derived neurotophic factor, BDNF) oder die Hypothalamus- Hypophysen-Nebennieren- (HPA) – Signalwege des Stressachsensystems. Ebenfalls wurde in Nagetiermodellen beobachtet, dass mit der Dysregulation des zentralen
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