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«Vorgelegt von Jakob Hartmann Juni 2014 Dissertation eingereicht am: 23. Juni 2014 Mündliche Prüfung am: 03. November 2014 1. Gutachter: PD. Dr. ...»

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Dissertation

an der Fakultät für Biologie

der Ludwig-Maximilians-Universität München

Vorgelegt von

Jakob Hartmann

Juni 2014

Dissertation eingereicht am: 23. Juni 2014

Mündliche Prüfung am: 03. November 2014

1. Gutachter: PD. Dr. Mathias V. Schmidt

2. Gutachter: Prof. Dr. Benedikt Grothe

3. Gutachter: Prof. Dr. Angelika Böttger

4. Gutachter: Prof. Dr. Jochen Heinrichs

5. Gutachter: Prof. Dr. Niels Dingemanse

6. Gutachter: Prof. Dr. Lutz Wiegrebe Table of Contents Table of Contents Table of Contents

Summary

Zusammenfassung

List of Abbreviations

1. General introduction

1.1. Mood and anxiety disorders

1.2. Modeling mood disorders in mice

1.3. Stress and stress response systems

1.4. The HPA axis

1.5. Corticoid receptors

1.6. Molecular chaperones and the hsp90 complex

1.7. The immunophilins FKBP51 and FKBP52

1.8. FKBP51 in human studies

1.9. FKBP51 in animal studies

1.10. FKBP51 as a drug target

2. Aim of the thesis

3. Research articles

3.1. The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress

Abstract

Introduction

Materials and Methods

Results

Discussion

Supplementary data

3.2. Depletion of FKBP51 in female mice shapes HPA axis activity

Abstract

Introduction

Materials and Methods

Results

Discussion

3.3. Fkbp52 heterozygosity alters behavioral, endocrine and neurogenetic parameters under basal and chronic stress conditions in mice

Abstract

ITable of Contents

Introduction

Materials and Methods

Results

Discussion

3.4. FKBP51 critically impacts antidepressant action and chronic stress recovery... 89 Abstract

Introduction

Materials and Methods

Results

Discussion

3.5. FKBP51 directs autophagic pathways, enabling prediction of antidepressant treatment response

Abstract

Introduction

Methods

Results

Discussion

Supplemental Materials and Methods

3.6. Pharmacological FKBP51 inhibition reduces anxiety-related behavior in mice141 Abstract

Introduction

Materials and Methods

Results

Discussion

Supplemental Figures

4. General discussion

4.1. GR-dependent functions of FKBP51

4.2. GR-independent functions of FKBP51

4.3. Implications for novel treatment options

4.4. Summary and future perspectives

5. Addendum

5.1. Glucocorticoid receptor in glutamatergic neurons controls anxiety................ 171 Abstract

Introduction

Materials and Methods

Results

II

Table of Contents

Discussion

Supplemental Figures

6. References

Curriculum Vitae

Publications

Acknowledgments

Assertion / Eidesstattliche Versicherung

–  –  –

Summary Chronic stress is a crucial risk factor for the development of numerous psychiatric diseases. One major finding in many depressed patients is an impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis, which is mediated via the glucocorticoid receptor (GR). FK506-binding protein 51 (FKBP51) has been shown to decrease ligand binding sensitivity of the GR, thereby directly affecting stress system (re)activity. Single nucleotide polymorphisms of FKBP51 have been linked to psychiatric disorders and antidepressant treatment response. Thus, FKBP51 has emerged as a novel potential drug target for the treatment of psychiatric disorders. This thesis aimed to investigate the function of FKBP51 as a mediator of the stress response system, its role in the development of stress related diseases and antidepressant responsiveness, as well as its potential as a novel treatment approach in psychiatric disorders. Therefore, I first subjected FKBP51 knockout mice to acute and chronic stress paradigms. Lack of FKBP51 resulted in a more stress-resistant phenotype, especially with regard to neuroendocrine parameters, which was most likely due to an enhanced GR sensitivity. Interestingly, mice lacking one allele of FKBP52 (FKBP52+/- mice), which is FKBP51’s close homologue and functional counter-player, demonstrated a mixed phenotype of stress susceptibility and resilience. Furthermore, FKBP51 knockout mice were less responsive to acute and chronic treatment of the antidepressant drug paroxetine. Searching for novel molecular actions of FKBP51 linked to antidepressant effects, we found that FKBP51 is involved in priming autophagic pathways, which are necessary for full antidepressant potency. In addition, I also investigated brain-region specific functions of FKBP51, by overexpressing the gene via virus-mediated gene transfer. While FKBP51 overexpression in the dorsal hippocampus did not result in a strong phenotype, mice with an overexpression in the basolateral amygdala showed an increased anxiety-related behavior. Interestingly, I could also demonstrate that pharmacological inhibition of FKBP51 resulted in an anxiolytic phenotype in mice. Thus, the findings presented in this thesis provide a strong basis for further research investigating the role of FKBP51 in psychiatric disorders and might pave the way for drug development of selective FKBP51 inhibitors.





–  –  –

Zusammenfassung In den letzten Jahren wurde eine Reihe von Studien veröffentlicht, die genetische Varianten (Einzelnukleotid-Polymorphismen) des Gens FKBP51 mit dem Auftreten von psychiatrischen Erkrankungen wie der Depression, sowie mit der Responsivität für Antidepressiva assoziieren. Das molekulare Co-Chaperon FKBP51 reguliert die Signaltransduktion von Steroidhormonrezeptoren, wie z. B. dem Glukokortikoidrezeptor (GR), welcher ein wichtiger Mediator der hormonellen Stressantwort über die Hypothalamus-HypophysenNebennieren (HHN) Achse des Körpers ist. Dabei verringert FKBP51 die Bindungsaffinität des GR für Stresshormone (Cortisol bei Menschen und Corticosteron bei Mäusen). Ein wiederholt auftretender Befund bei vielen psychiatrischen Erkrankungen wie der Depression ist eine Störung der HHN-Achse. FKBP51 rückte deshalb als potentielles neues Zielprotein zur Behandlung von psychiatrischen Erkrankungen vermehrt in den Fokus der Forschung. In der vorliegenden Arbeit untersuche ich die zugrundeliegenden Effekte von FKBP51 auf das Stresssystem im Körper und seine Verwicklung in psychiatrischen Erkrankungen. Hierfür habe ich transgene Mäuse, denen das FKBP51 Gen fehlt (FKBP51 knockout Mäuse), verschiedenen akuten und chronischen Stressoren ausgesetzt. Ich konnte zeigen, dass FKBP51 knockout Männchen und Weibchen eine geringere Stressanfälligkeit aufweisen als Kontrollmäuse, was vor allem durch die stets sehr niedrigen Corticosteronwerte deutlich wurde und auf eine verbesserte negative Rückkopplung der HHN-Achse schließen lässt. Um das molekulare Umfeld von FKBP51 weiter zu verstehen, habe ich außerdem seinen wichtigsten molekularen Gegenspieler und engsten Verwandten, das FKBP52, näher untersucht. Ich konnte zeigen, dass Mäuse mit nur einem Allel für FKBP52 (ein kompletter FKBP52-Knockout ist letal), in manchen Parametern stressanfälliger waren, bemerkbar z. B. durch erhöhtes Angstverhalten, gleichzeitig zeugten geringe basale Corticosteronwerte aber auch von einer gewissen Stressresistenz. Auf Grund der genetischen Assoziation zwischen FKBP51 Einzelnukleotid-Polymorphismen und Antidepressiva-Responsivität in klinischen Studien, unterzog ich FKBP51 Knockout Mäuse außerdem einer akuten und chronischen Behandlung des Antidepressivums Paroxetin.

Hierbei konnte ich zeigen, dass FKBP51 knockout Mäuse weniger auf Paroxetin reagieren.

Dieses Ergebnis spiegelt die klinische Situation wider, in der depressive Patienten mit erhöhten FKBP51 Werten schneller auf Antidepressiva reagieren. Wir konnten daraufhin VI

Zusammenfassung

neue FKBP51-abhänginge Signalwege der Autophagie identifizieren, über die Antidepressiva (neben ihrer gängigen Funktion zur Verstärkung der Wirkung von Neurotransmittern) alternativ wirken können. Um FKBP51 als mögliches Zielprotein zur Behandlung von psychiatrischen Erkrankungen weiter zu validieren, habe ich außerdem Hirnregionspezifische Funktionen des Co-Chaperons untersucht. So konnte ich zum Beispiel zeigen, dass eine Virus-vermittelte Überexpression von FKBP51 in der basolateralen Amygdala zu erhöhtem Angstverhalten in Mäusen führt. Ich konnte zudem zeigen, dass die Verabreichung von kürzlich entwickelten FKBP51 Antagonisten zu verringertem Angstverhalten in Mäusen führt. Die vorliegende Arbeit bietet daher eine exzellente Grundlage für weitere Forschungsarbeiten, die sich mit der Rolle von FKBP51 in psychiatrischen Erkrankungen beschäftigen und ebnet den Weg für die Entwicklung von Antidepressiva mit neuen Wirkmechanismen.

–  –  –

1. General introduction

1.1. Mood and anxiety disorders Every year more than a third of the population in the European Union (EU) suffers from brain disorders. Adjusted to age and comorbidity, this corresponds to 164.8 million persons affected, with mood disorders (7.8 %), such as major depression, and anxiety disorders (14.0 %), such as generalized anxiety disorder and post-traumatic stress disorder (PTSD), being the most frequent disorders (Wittchen et al., 2011). Interestingly, women are more susceptible to develop these diseases than men (Solomon and Herman, 2009;

Bangasser, 2013). The total EU cost burden of disorders of the brain for both genders was estimated at €798 billion in 2010, of which €113.4 billion were attributed to mood disorders and €74.4 billion to anxiety disorders. These numbers highlight that disorders of the brain must be considered to be Europe’s foremost health care challenge of the 21st century (Gustavsson et al., 2011).

Clinical depression refers to a condition of intense sadness, melancholia or despair, accompanied by anhedonia (loss of interest or pleasure), irritability, cognitive disturbances and abnormalities in appetite and sleep (Krishnan and Nestler, 2008). The condition can be chronic, with periods of good health interspersed with relapses; the recurrence of depressive episodes tends to increase over time, with increasing severity of each successive bout of illness (Yu et al., 2008). The diagnosis of depression is based on the documentation of a certain number of symptoms that significantly impair functioning for a certain duration. These diagnostic criteria overlap with other conditions such as anxiety disorders, which have substantial co-morbidity with depression (Nestler et al., 2002; Rocha et al., 2013).

Although antidepressant drugs are the most effective treatment for depressive disorders, pharmacotherapy still suffers from modest efficacy, the delayed onset of clinical improvement and high relapse rates. Despite intensive efforts in the development of antidepressants, major breakthroughs have only been achieved on the reduction of side effects of these drugs. Treatment efficacy can be enhanced by a combination of different General introduction antidepressant drugs, but adequate therapy response rates, i.e. full remission, are yet to be reached (Binder and Holsboer, 2006; Thase, 2006).

Epidemiologic as well as family and twin studies show that there is a substantial genetic risk to develop depression with an estimated heritability, i.e. genetic factors, of 30% to 40% (Fava and Kendler, 2000). However, depression is a complex phenomenon, as these studies also point to a polygenetic nature of the disorder, which implies that individual genes are likely to exert only a relatively small effect and that the interaction of several genes with each other determines the phenotype (Nestler et al., 2002; Klengel and Binder, 2013b). In addition, susceptibility to depression is only partly genetic, with environmental factors also being important. Exposure to aversive life events, such as traumatic experiences and chronic stress have consistently been established in the pathophysiology of this disorder (McEwen, 2004; Chrousos, 2009). The childhood period seems to be particularly sensitive to negative environmental factors, such as early life stress or child abuse, that increase the risk to develop depression later in life (Heim et al., 2010; Rocha et al., 2013).

It is important to note that depression is a multifactorial disease. A genetic predisposition or environmental risk factor per se is not sufficient to cause depression. It is generally accepted that in most people, depression is caused by interactions between a genetic predisposition and some environmental factors. Thus, studies investigating gene x environment interactions that aim at assessing the joint contribution of genetic and environmental factors for developing depression are an important focus of recent research in the field of mood disorders (Nestler et al., 2002; Klengel and Binder, 2013b).

However, knowledge about the molecular neurobiology of depression is rather rudimentary compared to knowledge of other common chronic and potentially fatal multifactorial diseases such as type 2 diabetes, due to the fact that observing pathological alterations within the brain remains markedly more difficult than for all other organs (Krishnan and Nestler, 2008). To further elucidate the complex nature of mood disorders, mouse models have proven extremely useful not only regarding the validation of neurobiological underpinnings, but also with respect to the identification and improvement of therapeutic substances (Nestler and Hyman, 2010).

–  –  –



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