LOSS OF GLUTAMIC ACID DECARBOXYLASE (Gad67) IN STRIATAL NEURONS EXPRESSING THE Drdr1a DOPAMINE RECEPTOR PREVENTS L-DOPA-INDUCED DYSKINESIA IN 6-HYDROXYDOPAMINE-LESIONED MICE

The objective in this study was to test the hypothesis that the GABA-synthesizing enzyme, glutamic acid decarboxylase (Gad67), expressed in striatal neurons plays a key role in dyskinesia induced by L-DOPA (LID) in a rodent model of Parkinson's disease. In light of evidence that the dopamine Drd1a receptor is densely expressed in striatal direct pathway striatal neurons while the orphan G-protein-coupled receptor Gpr88 is densely expressed in striatal direct and indirect pathway striatal neurons, we used a cre-lox strategy to produce two lines of mice that were Gad1 (Gad1 is the gene encoding for Gad67)-deficient in neurons expressing the Drd1a or the Gpr88 receptor. Gad67 loss in Gpr88-expressing neurons mice did not result in gross motor abnormalities while mice with Gad67 loss in Drd1a-expressing neurons were impaired on the Rotarod and the pole test. Knockout and control littermate mice were unilaterally injected into the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) in order to lesion dopamine neurons on one side of the brain. 6-OHDA-lesioned mice were then injected once daily for 10 days with L-DOPA. Mice with a Gad67 loss in Gpr88-expressing neurons and control littermates developed abnormal involuntary movements (AIM), a measure of dyskinesia. In contrast, mice with a Gad67 loss in Drd1a-expressing did not develop AIM. The results demonstrate that Gad67 in Drd1a-expressing neurons plays a key role in the development of LID and they support the hypothesis that altered GABAergic neurotransmission in the direct pathway is involved in dyskinesia. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.