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

Il Hwan Kim, Mark A. Rossi, Dipendra K. Aryal, Bence Racz, Namsoo Kim, Akiyoshi Uezu, Wang Fan, William C. Wetsel, Richard J. Weinberg, Henry Yin, Scott H. Soderling

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)883-891
Number of pages9
JournalNature Neuroscience
Volume18
Issue number6
DOIs
StatePublished - Jun 28 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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