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Plasticity Based Strategies for the Treatment of Depression

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Plasticity Based Strategies for the Treatment of Depression Thèse de Doctorat de l’Université Paris Descartes – Paris V Ecole Doctorale Médicament « de la molécule à la clinique » Plasticity Based Strategies for the Treatment of Depression Presenté par Kalliopi APAZOGLOU Date de soutenance prévue : 6 janvier 2012 Membres du jury: Mme le Professeur Christiane GARBAY Présidente M le Docteur Jean-Jacques BENOLIEL Rapporteur M le Professeur Patrice BOYER Rapporteur M le Professeur Rafael MALDONADO Examinateur M le Professeur Bruno GIROS Directeur de Thèse Mme le Docteur Eleni TZAVARA Directrice de Thèse The work presented in this thesis is relevant to the following patent applications: A European Patent Application n° EP 05290363605430 was filed by the UPMC and the CNRS on 17th February 2005, entitled « Intracellular inhibiting peptides » and naming Jocelyne CABOCHE and Peter VANHOUTTE as inventors. Regarding this invention, a PCT Application n° PCT EP 2006002068 all claiming priority of the European Patent Application has been filed on February 16th, 2006 and has been extended in USA, Japan and Canada. These peptides provided by Drs Caboche and Vanhoutte were used in this thesis in a collaborative study. A European Patent Application n° EP 08305636 was filed by the UPMC and the CNRS on 3rd October 2008, on “Peptide and non peptide inhibitors of Elk-1 in mood disorders”, naming Jocelyne CABOCHE, Peter VANHOUTTE, Bruno GIROS and Eleni TZAVARA as inventors. This application was PCT extended on October 2009 (PCT EP 2006002068). The present thesis contains unpublished experimental data in direct relevance to the above patent. 2 Plasticity based targets for the treatment of depression Abstract Major depression is a devastating disease that affects up to 20% of world population and is classified today as a leading cause of disability-adjusted life years. Since late 50s with the serendipitous discovery of the first antidepressant agents, pathophysiology and therapeutics of depression are governed by the monoaminergic hypothesis. Monoaminergic-based treatment, although still in use today, was proven inefficient to treat a significant proportion of cases and presents a delayed onset of action. Recent research has unveiled an array of new mechanisms through which antidepressant medication helps restore neuronal plasticity and neurotransmission that is disrupted in mood disorders and in animal models of depression. Glutamatergic transmission, in particular AMPA receptor, and signal transduction cascades have been implicated both in antidepressant action and the pathophysiology of depression, as here and now regulators that mediate persistent changes. In this study, AMPA receptors positive modulators demonstrated antidepressant-like effects in a chronic model of depression and preliminary data suggest a faster onset of action than conventional antidepressants. The ERK/MAPK signaling pathway was also studied as a major integrator of synaptic plasticity modifications that links extracellular signals to gene expression regulation via its downstream molecular partners. We used a new class of inhibitors of the ERK pathway, whose design was based on the particular property of ERK to bind to its downstream targets via specific docking domains. A considerable amount of data provided evidence for an antidepressant action of selective inhibition of the ERK/Elk1 signaling complex in multiple animal models of depression. Overall, the findings of this work reveal novel, promising targets for the treatment of depression. 3 CONTENTS INTRODUCTION ...................................... .......................... 7 DEPRESSIVE DISORDERS : DIAGNOSIS AND THERAPEUTICS ..................................... 7 I. CLINICAL CHARACTERISTICS .................................................................................................................. 8 a) Depressive Episode ................................ ................................................... .................... 8 b) Depression: a group of illnesses .................. ................................................... ............... 10 c) Comorbidity ....................................... ................................................... ..................... 11 II. CURRENT ANTIDEPRESSANT TREATMENT ........................................................................................... 15 ANIMAL MODELS OF DEPRESSION .............................................................. 20 I. STRESS-BASED MODELS ....................................................................................................................... 21 a) Models of construct or etiologic validity ............................................................ ............ 21 b) Models of high predictive validity ................ ................................................... .............. 23 c) Tests with high face validity ..................... ................................................... ................. 25 II. NEWER DIRECTIONS IN ANIMAL MODELS OF DEPRESSION ................................................................ 27 PATHOPHYSIOLOGY OF DEPRESSION : MONOAMINES AND BEYOND ......................... 28 I. MONOAMINES ..................................................................................................................................... 28 II. HYPOTHALAMO-PITUITARY-ADRENOCORTICAL (HPA) AXIS ................................................................ 31 a) Glucocorticoids and CNS ........................... ................................................... ................ 31 b) HPA dysfunction in depression ..................... ................................................... .............. 32 c) Glucocorticoid receptors (GRs) signaling ............................................................. ........... 34 III. INFLAMMATION AND DEPRESSION: CYTOKINES ................................................................................. 37 IV. CIRCADIAN SYSTEM: MELATONIN ....................................................................................................... 40 V. HYPOTHALAMIC FEEDING PEPTIDES - NEUROPEPTIDES ..................................................................... 42 VI. GLUTAMATERGIC HYPOTHESIS OF DEPRESSION ................................................................................. 43 VII. NEUROTROPHIN HYPOTHESIS: BDNF .................................................................................................. 43 a) BDNF protein ...................................... ................................................... ..................... 44 b) BDNF in depression ................................ ................................................... .................. 45 c) BDNF in distinct brain systems and networks .......................................................... ........ 47 d) Hippocampal atrophy: Glucocorticoids - Glutamate – BDNF .............................................. 49 FROM GENES TO PLASTICITY AND BACK : CURRENT CONCEPTS IN THE PATHOPHYSIOLOGY OF DEPRESSION ...................................................................... 52 I. GENETICS OF DEPRESSION .................................................................................................................. 52 II. EPIGENETIC MODIFICATIONS .............................................................................................................. 54 III. RESILIENCE AND SYNAPTIC PLASTICITY: SIGNAL TRANSDUCTION PATHWAYS ................................... 56 a) The cAMP second messenger system ..................................................................... ......... 56 b) The phosphoinositol cycle ......................... ................................................... ................ 58 c) The GSK-3 signaling pathway ....................... ................................................... .............. 59 d) Mitogen-activated protein kinases (MAPKs) ............................................................ ........ 61 AIM OF THE STUDY .................................. ........................ 67 MATERIALS AND METHODS ............................. ................... 68 BEHAVIOURAL TESTS ............................................................................. 68 I. MODELS OF DEPRESSION .................................................................................................................... 68 a) Social defeat stress .............................. ................................................... .................... 68 b) Unpredictable chronic mild stress ................. ................................................... ............. 70 II. TESTS OF HIGH FACE VALIDITY ............................................................................................................ 71 III. TESTS OF HIGH PREDICTIVE VALIDITY .................................................................................................. 73 4 IV. COGNITIVE TESTING ............................................................................................................................ 75 BIOCHEMICAL APPROACHES ..................................................................... 77 I. IMMUNOHISTOCHEMISTRY ................................................................................................................. 77 II. IN SITU HYBRIDIZATION ....................................................................................................................... 77 III. SYNAPTOSOMAL FRACTION PREPARATION........................................................................................
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