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Disentangling the Role of SHANK1 in a Mouse Model for Autism Spectrum Disorder: from Brain to Behavior

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Disentangling the Role of SHANK1 in a Mouse Model for Autism Spectrum Disorder: From Brain to Behavior Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) dem Fachbereich Psychologie der Philipps-Universität Marburg vorgelegt von Ayşe Özge Sungur aus Trabzon, Türkei Marburg, 2017 Vom Fachbereich Psychologie der Philipps-Universität Marburg als Dissertation am 27.09.2017 angenommen. Erstgutachter: Dr. Markus Wöhr, Philipps-Universität Marburg Zweitgutachter: Prof. Dr. Sören Krach, Universität zu Lübeck Tag der mündlichen Prüfung: 27.09.2017 i TABLE OF CONTENTS SUMMARY 1 ZUSAMMENFASSUNG 2 1 INTRODUCTION 3 1.1 Autism Spectrum Disorder ..................................................................................................... 3 1.1.1 Genetics of ASD ............................................................................................................ 6 1.1.2 Synaptic Pathways and ASD ......................................................................................... 9 1.2 SHANK Family of Proteins .................................................................................................. 11 1.2.1 Shankopathies in ASD ................................................................................................. 13 1.3 Animal Models of ASD ........................................................................................................ 15 1.3.1 Testing ASD in Animal Models .................................................................................. 15 Social interaction ................................................................................................................ 16 Communication ................................................................................................................... 17 Repetitive behaviors ........................................................................................................... 19 1.3.2 Shank1 Mouse Model for ASD ................................................................................... 20 2 OBJECTIVES AND HYPOTHESES 22 3 SUMMARY OF PUBLICATIONS 24 Study I: Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post-synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder .................................................................................. 24 Study II: Early communication deficits in the Shank1 knockout mouse model for autism spectrum disorder: Developmental aspects and effects of social context .................................... 25 Study III: Repetitive behaviors in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context .................................................... 26 ii 4 GENERAL DISCUSSION 28 4.1 Shank1 Deletion Leads to ASD-Like Behavioral Phenotypes throughout Development .... 28 4.2 Social Context Plays a Crucial Role in Eliciting ASD-Like Behavioral Phenotype in Shank1 Knockout Mice ................................................................................................................ 32 4.3 Cognitive Deficits in Shank1 Knockout Mice ...................................................................... 33 4.4 Neurobiological Alterations in Shank1 Knockout Mice ....................................................... 34 4.5 Phenotype of Shank1 Knockout Mice - Summary ............................................................... 37 4.6 Shank1 Mouse Model for ASD: A Translational Perspective .............................................. 37 4.7 Future Perspectives ............................................................................................................... 39 4.8 Concluding Remarks ............................................................................................................. 40 5 PUBLICATIONS 42 Study I: Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post-synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder .................................................................................. 42 Study II: Early communication deficits in the Shank1 knockout mouse model for autism spectrum disorder: Developmental aspects and effects of social context .................................... 58 Study III: Repetitive behaviors in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context .................................................... 75 6 APPENDIX 85 6.1 SHANK1 – Gene and Protein Nomenclature ....................................................................... 85 6.2 Abbreviations ........................................................................................................................ 85 7 REFERENCES 87 ACKNOWLEDGEMENTS 100 CURRICULUM VITAE 101 ERKLÄRUNG 106 iii Summary SUMMARY Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by persistent deficits in social communication and interaction across multiple contexts, and restricted, repetitive patterns of behavior; frequently comorbid with intellectual disability (ID). Several studies highlight immense contribution of genetic factors to disease etiology. Particularly, the SHANK family of postsynaptic proteins has emerged as promising candidates, considering that mutations in SHANK1, SHANK2, and SHANK3 genes have repeatedly been reported in individuals with ASD. Animal models provide excellent translational tools to discover disease pathogenesis underlying behavioral and neurobiological abnormalities. This dissertation aimed at understanding these mechanisms by using the Shank1 knockout mouse model for ASD, with an in-depth and longitudinal focus on each diagnostic symptom. Specifically, ASD-like phenotypes were investigated throughout development and across different social contexts. While social behavior was only moderately affected in mice lacking SHANK1 (Study I), evidence for communication deficits and repetitive behavior throughout development and/or across different social contexts were demonstrated in these animals (Study II&III). In conjunction with ASD – ID comorbidity, deletion of Shank1 resulted in severe cognitive impairments (Study I). Highlighting the pivotal role of the hippocampus in this mechanism, elevated levels of learning-associated brain-derived neurotrophic factor were found in the hippocampi of Shank1 mutants. This increase in protein expression was paralleled by alterations in epigenetic regulation (Study I). Overall, results of the studies presented here indicate that SHANK1 is involved in ASD-relevant deficits across species. These findings further extend the knowledge on social communication and interaction, repetitive behaviors, and cognitive phenotypes displayed by the Shank1 mouse model for ASD in an age- and sex- dependent manner, underscoring the importance of social context in ASD research. - 1 - Zusammenfassung * ZUSAMMENFASSUNG Autismus-Spektrum- Störungen (ASS) gehören zu einer Gruppe von Entwicklungsstörungen des Nervensystems. Diese Störungen zeichnen sich durch anhaltende Abweichungen der sozialen Kommunikation und Interaktion in verschiedenen Kontexten und durch eingeschränkte, repetitive Verhaltensmustern aus. Häufig tritt eine Komorbidität mit mentalen Retardierungen auf. Viele Studien konnten eine genetische Ursache für die Entstehung dieser Krankheit verantwortlich machen. Besonders Mutationen einer Familie postsynaptischer Proteine, den SHANKs, haben sich dabei als wahrscheinliche Grundlage dieser genetischen Ursache herausgestellt, da verschiedene SHANK-Mutationen gehäuft in ASS-Patienten auftreten. Tiermodelle bieten eine effektive Möglichkeit, die genetischen Ursachen, die der Entstehung dieser Krankheit zugrunde liegen mit Verhaltensauffälligkeiten zu korrelieren. In dieser Dissertation wurde die Rolle von SHANK1 in der Entstehung von ASS-assoziierten Symptomen in unterschiedlichen sozialen Kontexten während der Entwicklung in einem Shank1 knockout Mausmodell untersucht. Während ein Shank1 knockout auf das murine Sozialverhalten nur einen mäßigen Einfluss hat (Studie I), entwickelten diese Mutanten in verschiedenen sozialen Kontexten Kommunikationsdefizite und repetitives Verhalten (Studie II&III). Darüber hinaus deutet Studie I darauf hin, dass SHANK1 eine Rolle bei der Komorbidität von ASS und der mentalen Retardierung spielt, da ein Shank1 Knockout zu kognitiven Beeinträchtigungen führte. Diese kognitive Beeinträchtigung korrelierte mit einer erhöhten Expression von mit Lernen assoziiertem BDNF im Hippocampus, was die herausragende Rolle des Hippocampus in diesem Zusammenhang unterstreicht. Die erhöhte BDNF Expression ging weiterhin mit epigenetischen Veränderungen einher (Studie I). Zusammengefasst deuten diese Resultate auf eine Beteiligung einer Shank1 Mutation bei der Entstehung ASS-assoziierter Defizite in der Maus hin. Diese Ergebnisse tragen zum Verständnis der Rolle von SHANK1 bei der alters- und geschlechtsabhängigen Entstehung von Abweichungen der sozialen Kommunikation und Interaktion, repetitivem Verhalten, und kognitiven Defiziten bei und unterstreichen dadurch die Bedeutung des sozialen Kontexts bei der Erforschung von ASS. * My sincerest gratitude goes to Philipp Gobrecht for his extensive help in this translation. - 2 - Introduction 1 INTRODUCTION 1.1 Autism Spectrum Disorder In 1911, the Swiss psychiatrist Eugen Bleuler was first to introduce
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  • Synaptic Pathways Related to Shank3 and Its Interaction Partner Prosapip1

    Synaptic Pathways Related to Shank3 and Its Interaction Partner Prosapip1

    International Graduate School in Molecular Medicine Ulm International PhD Programme in Molecular Medicine Synaptic pathways related to Shank3 and its interaction partner ProSAPiP1 Dissertation submitted in partial fulfilment of the requirements for the degree of „Doctor rerum naturalium” (Dr. rer. nat.) of the International Graduate School in Molecular Medicine Ulm Dominik Reim Born in Nürtingen, Germany Institute for Anatomy and Cell Biology, Head: Prof. Dr. Tobias M. Böckers 2016 1. Current dean / chairman of the Graduate School: Prof. Dr. Michael Kühl 2. Thesis Advisory Committee: - First supervisor: Prof. Dr. Tobias M. Böckers - Second supervisor: Prof. Dr. Thomas Wirth - Third supervisor: Dr. Chiara Verpelli 3. External reviewer: Prof. Dr. Matthias Kneussel 4. Day doctorate awarded: March 20, 2017 Results gained in my thesis have previously been published in the following publications: Reim, D., Distler, U., Halbedl, S., Verpelli, C., Sala, C., Bockmann, J., Tenzer, S., Boeckers, T.M., and Schmeisser, M.J. (2017). Proteomic analysis of postsynaptic density fractions from Shank3 mutant mice reveals brain region specific changes relevant to autism spectrum disorder. Front Mol Neurosci, doi: 10.3389/fnmol.2017.00026 Reim, D., Weis, T.M., Halbedl, S., Delling, J.P., Grabrucker, A.M., Boeckers, T.M., and Schmeisser, M.J. (2016). The Shank3 Interaction Partner ProSAPiP1 Regulates Postsynaptic SPAR Levels and the Maturation of Dendritic Spines in Hippocampal Neurons. Front Synaptic Neurosci 8, 13, doi: 10.3389/fnsyn.2016.00013 Vicidomini, C., Ponzoni, L., Lim, D., Schmeisser, M.J., Reim, D., Morello, N., Orellana, D., Tozzi, A., Durante, V., Scalmani, P., Mantegazza, M., Genazzani, A.A., Giustetto, M., Sala, M., Calabresi, P., Boeckers, T.M., Sala, C., and Verpelli, C.
  • Using Gene Ontology to Describe the Role of the Neurexin-Neuroligin-SHANK Complex in Human, Mouse and Rat and Its Relevance to Autism Patel Et Al

    Using Gene Ontology to Describe the Role of the Neurexin-Neuroligin-SHANK Complex in Human, Mouse and Rat and Its Relevance to Autism Patel Et Al

    Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism Patel et al. Patel et al. BMC Bioinformatics (2015) 16:186 DOI 10.1186/s12859-015-0622-0 Patel et al. BMC Bioinformatics (2015) 16:186 DOI 10.1186/s12859-015-0622-0 METHODOLOGY ARTICLE Open Access Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism Sejal Patel1,2,3, Paola Roncaglia4,5 and Ruth C. Lovering3* Abstract Background: People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders. Results: In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database. Conclusions: The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained throughgenomewideassociationstudies, next generation sequencing, proteomic and transcriptomic datasets.