Journal
NATURE NEUROSCIENCE
Volume 18, Issue 6, Pages 883-U326Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4015
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Funding
- US National Institutes of Health (NIH) [MH103374, NS059957]
- NIH [NS077986, AA021074, NS039444, MH082441]
- US National Research Foundation
- Hungarian Academy of Sciences
- Hungarian Scientific Research Fund (OTKA) [K83830]
- Szent Istvan University, Faculty of Veterinary Science
- North Carolina Biotechnology Center grant
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Psychiatric and neurodevelopmental disorders may arise from anomalies in long-range neuronal connectivity downstream of pathologies in dendritic spines. However, the mechanisms that may link spine pathology to circuit abnormalities relevant to atypical behavior remain unknown. Using a mouse model to conditionally disrupt a critical regulator of the dendritic spine cytoskeleton, the actin-related protein 2/3 complex (Arp2/3), we report here a molecular mechanism that unexpectedly reveals the inter-relationship of progressive spine pruning, elevated frontal cortical excitation of pyramidal neurons and striatal hyperdopaminergia in a cortical-to-midbrain circuit abnormality. The main symptomatic manifestations of this circuit abnormality are psychomotor agitation and stereotypical behaviors, which are relieved by antipsychotics. Moreover, this antipsychotic-responsive locomotion can be mimicked in wild-type mice by optogenetic activation of this circuit. Collectively these results reveal molecular and neural-circuit mechanisms, illustrating how diverse pathologies may converge to drive behaviors relevant to psychiatric disorders.
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