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Behavioral and Synaptic Consequences Following Removal of the Il1rapl1 Gene in Mice, a Model of Intellectual Disability

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Behavioral and Synaptic Consequences Following Removal of the Il1rapl1 Gene in Mice, a Model of Intellectual Disability THESE Pour le DOCTORAT De L’UNIVERSITE DE BORDEAUX Ecole Doctorale des Sciences de la Vie et de la Santé Présentée et soutenue publiquement Le 28 novembre 2014 Par Xander Houbaert Behavioral and synaptic consequences following removal of the Il1rapl1 gene in mice, a model of intellectual disability Membres du Jury M. le Dr. Bertrand Lambolez (DR CNRS)…………………………… (rapporteur externe) M. le Dr Nael Nadif Kasri (Assistant Professor)………………… (rapporteur externe) M. le Dr. Carlo Sala (Senior Researcher)..………………………… (examinateur) M. le Dr. Cyril Herry (CR Inserm)……………………………………… (examinateur) M. le Dr. Yann Humeau (CR CNRS)…………………………………… (directeur de thèse) Table of contents I) Remerciements ................................................................... 1 II) Résumé en français ............................................................ 3 III) Abstract en français ........................................................... 6 IV) Abstract .................................................................................. 7 V) Abbreviations ....................................................................... 8 VI) Introduction ...................................................................... 11 1 Intellectual disabilities ............................................................ 13 1.1 General definitions ............................................................................. 13 1.2 Function of ID-related genes ........................................................... 16 1.3 Physiology of the brain in health and disease .......................... 17 1.3.1 Synaptic integration ......................................................................................... 17 1.3.2 Synaptic function ............................................................................................... 21 1.3.2.1 Presynaptic function ....................................................................................................... 21 1.3.2.2 Postsynaptic function ...................................................................................................... 26 1.3.3 Brain development and ID ............................................................................. 31 1.3.3.1 Synaptogenesis .................................................................................................................. 32 1.4 Animal models of ID ........................................................................... 35 1.5 Towards ID therapeutics? ................................................................ 36 2 A model of intellectual disability: mutations in the Il1rapl1 gene ....................................................................................... 39 2.1 Structure of IL1RAPL1 ....................................................................... 39 2.2 IL1RAPL1 and ID in humans ............................................................ 40 2.3 Biological role of IL1RAPL1 ............................................................. 41 2.3.1 Presynaptic .......................................................................................................... 42 2.3.2 Postsynaptic ........................................................................................................ 43 2.3.3 Transsynaptic ..................................................................................................... 44 2.3.4 In vivo role of IL1RAPL1 .................................................................................. 46 3 Associative learning as a tool to measure cognition on an ID model ......................................................................................... 48 3.1 Fear conditioning ................................................................................ 48 3.2 Neuronal substrates ........................................................................... 49 3.2.1 The amygdala ...................................................................................................... 50 3.2.1.1 General anatomy and connectivity ............................................................................. 50 3.2.1.2 Cellular composition ........................................................................................................ 51 3.2.2 Hippocampus ...................................................................................................... 53 3.2.2.1 General anatomy .............................................................................................................. 53 3.2.2.2 Hippocampus in contextual coding............................................................................. 54 3.3 Synaptic plasticity in associative learning ................................. 56 3.3.1 Synaptic plasticity, general principles ....................................................... 57 3.3.2 Synaptic plasticity related to fear conditioning ..................................... 59 3.3.3 Modulation of synaptic plasticity by inhibitory cells ........................... 60 VII) Materials and methods .................................................. 62 1 Animals ......................................................................................... 62 2 Fear conditioning ...................................................................... 64 2.1 Cued fear conditioning ...................................................................... 64 2.2 Contextual fear conditioning .......................................................... 65 3 Optogenetics ............................................................................... 67 4 Surgeries ...................................................................................... 70 5 In vitro electrophysiology on acute brain slices ............. 71 5.1 Slice preparation ................................................................................. 71 5.2 Electrophysiological recordings .................................................... 73 5.3 Data acquisition and analysis ......................................................... 75 VIII) Results .............................................................................. 76 1 Publication 1: “Target-specific vulnerability of excitatory synapses leads to deficits in associative memory in a model of intellectual disorder” ............................................ 78 1.1 Results summary ................................................................................ 78 1.2 Discussion.............................................................................................. 82 1.3 Conclusion ............................................................................................. 86 2 Publication 2: “The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability ....................................................................... 88 2.1 Results summary ................................................................................ 88 2.2 Discussion.............................................................................................. 93 2.3 Conclusion ............................................................................................. 95 IX) General discussion .......................................................... 98 1 How and where does IL1RAPL1 absence impact the synapse? ............................................................................................ 100 1.1 IL1RAPL1, a synaptogenic protein .............................................. 100 1.1.1 Postsynaptic IL1RAPL1 mediates synapse formation/maintenance 101 1.1.2 Heterogeneity defines vulnerability to IL1RAPL1 absence ............. 103 1.1.3 Does IL1RAPL1 have a presynaptic function? ....................................... 106 1.1.4 A proteomic approach to study the consequence of IL1RAPL1 absence at the synapse ................................................................................................ 107 2 When is IL1RAPL1 important at the synapse? .............. 112 2.1 Consequences of IL1RAPL1’s absence on information processing and behavior? ......................................................................... 113 2.1.1 In vivo imaging as a tool to study synapse dynamics .......................... 113 2.1.2 Catching behaviorally relevant cells ........................................................ 114 X) Conclusion ............................................................................. 118 XI) Bibliography .................................................................... 119 I) Remerciements Je remercie sincèrement mon directeur de thèse, le Dr. Yann Humeau, de m’avoir offert la chance de rejoindre son équipe il y a de ça déjà presque quatre ans. Depuis, l’équipe et les projets scientifiques continuent de se diversifier et le fait d’assister et de participer à cette évolution fut très enrichissant. Je tiens à le remercier pour sa disponibilité et pour les nombreuses discussions que nous avons pu avoir au cours de ma thèse. Il a su m’initier au monde de l’électrophysiologie et me transmettre sa passion pour ce domaine. Un grand merci également pour la liberté qu’il m’a laissée afin de développer mes propres idées et expériences. Travailler avec lui fut un plaisir et j’espère que nos chemins se recroiseront dans l’avenir. J’oubliais presque, merci de m’avoir offert la possibilité de participer à de grands congrès scientifiques dont celui à Copenhague qui me tenait vraiment à cœur pour la recherche de mon futur post-doc. Je remercie également le directeur de l’Institut Interdisciplinaire
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