Striatal GluN2A gene suppression reduces L-DOPA-induced abnormal involuntary movements in parkinsonian rats.

Abstract

L-DOPA-induced dyskinesia (LID) is a common disabling complication of long-term L-DOPA therapy in Parkinson's disease (PD). LID development is associated with maladaptive plasticity mechanisms in striatal circuits contributed by dysregulated dopamine and glutamate signaling. Upregulation of the NMDAR subunit 2A (GluN2A) over chronic L-DOPA treatment is thought to play a role in corticostriatal synaptic changes. We investigated the motor effects of selective GluN2A gene silencing by injecting a shRNA vector in the striatum of hemiparkinsonian rats. Striatal GluN2A knockdown significantly reduced abnormal involuntary movements (AIMs) while sustaining the therapeutic benefit of L-DOPA. These findings suggest that targeted adjustments of striatal NMDAR subunit composition may be a promising strategy for managing the long-term therapy of PD.