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Nat Neurosci. 2015 Jun;18(6):883-91. doi: 10.1038/nn.4015. Epub 2015 May 4.

Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.

Author information

1
Department of Cell Biology, Duke University Medical School, Durham, North Carolina, USA.
2
Department of Psychology and Neuroscience, Duke University Medical School, Durham, North Carolina, USA.
3
1] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina, USA. [2] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina.
4
1] Department of Anatomy and Histology, Szent István University, Budapest, Hungary. [2] Faculty of Veterinary Science, Szent István University, Budapest, Hungary.
5
Department of Neurobiology, Duke University Medical School, Durham, North Carolina, USA.
6
1] Department of Cell Biology, Duke University Medical School, Durham, North Carolina, USA. [2] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina, USA. [3] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina. [4] Department of Neurobiology, Duke University Medical School, Durham, North Carolina, USA.
7
1] Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina, USA.
8
1] Department of Cell Biology, Duke University Medical School, Durham, North Carolina, USA. [2] Department of Neurobiology, Duke University Medical School, Durham, North Carolina, USA.

Abstract

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.

PMID:
25938885
PMCID:
PMC4459733
DOI:
10.1038/nn.4015
[Indexed for MEDLINE]
Free PMC Article

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