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

Kim, Il Hwan and Rossi, Mark A. and Aryal, Dipendra K. and Rácz, Bence and Kim, Namsoo (2015) Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine. NATURE NEUROSCIENCE, 18. pp. 883-891. ISSN 1097-6256

Text Soderling.NN2015.pdf - Published Version Restricted to Repository staff only Download (3MB) | Request a copy

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 antipsychoticresponsive 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.

Actions (login required)

Edit Item