Loss of glutamic acid decarboxylase (Gad67) in striatal neurons expressing the Drdr1a dopamine receptor prevents l-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned mice

- Loss of Gad67 in Drd1a-expressing neurons prevents l-DOPA-induced dyskinesia.
- Loss of Gad67 in Gpr88-expressing neurons does not prevent dyskinesia.
- Gad67 in striatal direct pathway mediates l-DOPA-induced dyskinesia.
- Gad67 in striatal indirect pathway neurons facilitates l-DOPA-induced dyskinesia.

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.