title: Loss of glutamic acid decarboxylase (Gad67) in striatal neurons expressing the Drdr1a dopamine receptor prevents L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned mice.
abstract: 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.
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chammas
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: jjsogho@bu.edu.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Soghomonian
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005968:Glutamate Decarboxylase / Q000172:deficiency* / Q000235:genetics; D007980:Levodopa / Q000009:adverse effects; D008474:Medial Forebrain Bundle / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D011597:Psychomotor Performance / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; C583261:Drd1 protein, mouse; C485998:Gpr88 protein, mouse; D017447:Receptors, Dopamine D1; D043562:Receptors, G-Protein-Coupled; C534628:SCH 23390; D007980:Levodopa; D016627:Oxidopamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: 6-hydroxydopamine; GABA; dyskinesia; levodopa; striatonigral; striatum