Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors

TLDR

The basal ganglia’s direct and indirect pathways are thought to oppositely regulate locomotion and contribute differently to pathological behaviors, but dissecting their distinct roles has been difficult. The study aimed to selectively disrupt striatonigral or striatopallidal neurons to examine their specific contributions to motor behavior. Two mouse models were generated with cell‑type–specific deletion of DARPP‑32 in striatonigral or striatopallidal neurons. Loss of DARPP‑32 in striatonigral neurons reduced basal and cocaine‑induced locomotion and eliminated L‑DOPA‑induced dyskinesia, whereas loss in striatopallidal neurons increased locomotion and markedly decreased haloperidol‑induced catalepsy, highlighting distinct pathway roles in motor control.

Abstract

The direct and indirect pathways of the basal ganglia have been proposed to oppositely regulate locomotion and differentially contribute to pathological behaviors. Analysis of the distinct contributions of each pathway to behavior has been a challenge, however, due to the difficulty of selectively investigating the neurons comprising the two pathways using conventional techniques. Here we present two mouse models in which the function of striatonigral or striatopallidal neurons is selectively disrupted due to cell type–specific deletion of the striatal signaling protein dopamine- and cAMP-regulated phosphoprotein Mr 32kDa (DARPP-32). Using these mice, we found that the loss of DARPP-32 in striatonigral neurons decreased basal and cocaine-induced locomotion and abolished dyskinetic behaviors in response to the Parkinson's disease drug L-DOPA. Conversely, the loss of DARPP-32 in striatopallidal neurons produced a robust increase in locomotor activity and a strongly reduced cataleptic response to the antipsychotic drug haloperidol. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors.