Expression of GAD65 and GAD67 immunoreactivity in MPTP-treated monkeys with or without L-DOPA administration

This study investigated the consequences of levodopa treatment on the expression of the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD65 and GAD67) immunoreactivity in the basal ganglia and cortex of monkeys rendered Parkinsonian by systemic MPTP administration. All MPTP-treated monkeys showed Parkinsonian impairment and selective loss of tyrosine hydroxylase (TH) with sparing of GAD immunoreactive (-ir) fibers and terminals in basal ganglia. The distribution of GAD65- and GAD67-ir in the cortex, caudate, and putamen was not significantly different in MPTP vs. naïve monkeys nor as a function of L-DOPA treatment. In comparison, the expression of GAD67- but not GAD65-ir was augmented in the globus pallidus in MPTP-treated monkeys. Quantification revealed significant increases in number of GAD67-ir neurons in the external and internal segments of the globus pallidus while no significant difference in the number of GAD65-ir neurons was observed. L-DOPA treatment did not significantly change the number of GAD65- or GAD67-ir pallidal neurons following MPTP. These results support and extend the findings that transcriptional elevation of GAD67 occurs in the globus pallidus and demonstrate that GAD65 and GAD67 are differentially altered following lesion. The finding of elevated GAD67 expression in the pallidum is consistent with alterations in inhibitory neurocircuitry playing a key role in the pathophysiology of motor disturbances in Parkinson's disease.