Genetische Grundlagen von Sozialverhalten und Ultraschallkommunikation: autismusähnlicher Phänotyp von Shank1-KO-Mäusen?
Final Report Abstract
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders of unknown etiology but high heritability. ASD is characterized by early-onset deficits in social behavior and communication across multiple contexts, together with restricted, repetitive patterns of behavior, interests, or activities. Genetics plays a key role in the etiology of ASD. In fact, ASD is among the most heritable neuropsychiatric conditions with heritability estimates higher than 80%, and while available evidence points to a complex set of genetic factors, the SHANK (also known as ProSAP) gene family has emerged as one of the most promising candidates. As part of the first funding period of the project WO 1732/1-1, we showed that the Shank1 mouse model for ASD displays impairments in (I) social behavior, (II) communication, and (III) repetitive and stereotyped patterns of behavior, together with (IV) aberrant cognitive phenotypes, consistent with the symptoms present in humans diagnosed with ASD and carrying SHANK1 deletions. Our neurobiological findings add to growing evidence linking dysregulation of activity-dependent signaling pathways and excitation/inhibition imbalance to ASD. Epigenetic modifications, microRNA manipulations, and upregulation of parvalbumin appear promising targets for future preclinical studies on pharmacological interventions in ASD.
Publications
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(2014). Ultrasonic vocalizations in Shank mouse models for autism spectrum disorders: Detailed spectrographic analyses and developmental profiles. Neuroscience and Biobehavioral Reviews, 43, 199-212
Wöhr, Markus
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(2015). Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morpho-functional abnormalities. Translational Psychiatry, 5, e525
Wöhr, M.; Orduz, D.; Gregory, P.; Moreno, H.; Khan, U.; Vörckel, K. J.; Wolfer, D. P.; Welzl, H.; Gall, D.; Schiffmann, S. N. & Schwaller, B.
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(2015). Reduced isolation-induced pup ultrasonic communication in mouse pups lacking brain serotonin. Molecular Autism, 6, e13
Mosienko, Valentina; Beis, Daniel; Alenina, Natalia & Wöhr, Markus
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(2016). Early communication deficits in the Shank1 knockout mouse model for autism spectrum disorder: Developmental aspects and effects of social context. Autism Research, 9, 696-709
Sungur, A. Özge; Schwarting, Rainer K.W. & Wöhr, Markus
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(2017). 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. Hippocampus, 27, 906-919
Sungur, A. Özge; Jochner, Magdalena C.E.; Harb, Hani; Kılıç, Ayşe; Garn, Holger; Schwarting, Rainer K.W. & Wöhr, Markus
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(2018). 17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms. Molecular Autism, 9, e15
Filice, Federica; Lauber, Emanuel; Vörckel, Karl Jakob; Wöhr, Markus & Schwaller, Beat
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(2018). Reduced efficacy of d-amphetamine and 3,4-methylenedioxymethamphetamine in inducing hyperactivity in mice lacking the postsynaptic scaffolding protein SHANK1. Frontiers in Molecular Neuroscience, 11, e419
Sungur, A. Özge; Redecker, Tobias M.; Andres, Elena; Dürichen, Wiebke; Schwarting, Rainer K. W.; del Rey, Adriana & Wöhr, Markus
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(2019) A placental mammal-specific microRNA cluster acts as a natural brake for sociability in mice. EMBO reports 20 (2) e46429
Lackinger, Martin; Sungur, A Özge; Daswani, Reetu; Soutschek, Michael; Bicker, Silvia; Stemmler, Lea; Wüst, Tatjana; Fiore, Roberto; Dieterich, Christoph; Schwarting, Rainer KW; Wöhr, Markus & Schratt, Gerhard
