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Disentangling the Role of SHANK1 in a Mouse Model for Autism Spectrum Disorder: From Brain to Behavior
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 hig...
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| Format: | Doctoral Thesis |
| Language: | English |
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Philipps-Universität Marburg
2017
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| Online Access: | PDF Full Text |
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| 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. |
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| DOI: | 10.17192/z2017.0672 |