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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin-Related Protein 3 / genetics
  • Actin-Related Protein 3 / metabolism
  • Angiopoietin-like Proteins
  • Angiopoietins / genetics
  • Angiopoietins / metabolism
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Dendritic Spines / physiology*
  • Dopamine / metabolism*
  • Female
  • Locomotion / drug effects*
  • Male
  • Mesencephalon / drug effects
  • Mice
  • Mice, Knockout
  • Mutation
  • Neostriatum / drug effects
  • Neostriatum / metabolism*
  • Nerve Net / drug effects
  • Nerve Net / metabolism*
  • Optogenetics
  • Patch-Clamp Techniques
  • Prefrontal Cortex / drug effects
  • Psychomotor Agitation / psychology
  • Pyramidal Cells / drug effects
  • Stereotyped Behavior / drug effects

Substances

  • Actin-Related Protein 3
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Angptl2 protein, mouse
  • Antipsychotic Agents
  • Dopamine