Increased glutamate decarboxylase mRNA levels in the striatum and pallidum of MPTP-treated primates

Abstract

The mRNA levels encoding for the enzyme glutamate decarboxylase (GAD67) were measured by computerized image analysis after in situ hybridization histochemistry and radioautography in the striatum and pallidum of normal squirrel monkeys (Saimiri sciureus), or after treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). All MPTP-injected monkeys exhibited profound motor deficits including akinesia. The dopaminergic innervation, as visualized and quantified on x-ray films after 3H-mazindol binding on tissue sections, was uniformly lost throughout the striatum of MPTP- treated monkeys. Brain sections processed with a probe synthesized from a feline or human GAD67 cDNA exhibited intense radioautographic labeling throughout the striatum. When measured on x-ray films, the intensity of GAD67 mRNA labeling was increased in the striatum of MPTP- treated versus control monkeys. Increased labeling reached statistical significance in the dorsolateral sector of the rostral putamen and throughout the putamen and the caudate at the caudal, postcommissural, level. Analysis of emulsion radioautographs demonstrated that the increase in GAD67 mRNA labeling in MPTP-treated monkeys occurred in individual neurons of the striatum. In the external and internal segments of the pallidum, numerous neurons labeled with the GAD67 cRNA probe were visualized on emulsion radioautographs. The intensity of GAD67 mRNA labeling in single neurons of both pallidal segments was increased in MPTP-treated versus control monkeys. Construction of the histograms of frequency distribution of labeling indicated that this increase occurred in a majority of labeled neurons. The present study demonstrates that GAD67 mRNA levels are significantly altered in the striatum and pallidum of parkinsonian monkeys. The preferential increase of GAD67 mRNA labeling in the dorsolateral putamen, which receives afferents from the sensorimotor cortex, provides further evidence of the involvement of GABAergic transmission in the expression of the motor deficits elicited after MPTP. In addition, increased GAD67 mRNA levels in the internal segment of the pallidum support the hypothesis of an increased activity of GABAergic neurons in the output structures of the basal ganglia in parkinsonism.

Glutamate decarboxylase (GAD67 and GAD65) gene expression is increased in a subpopulation of neurons in the putamen of parkinsonian monkeys

“…As previously reported Soghomonian et al, 1994), the intensity of labeling with the radioactive GAD67 or GAD65 probes was higher in MPTP-treated than in control monkeys (Figs. 3, 4).…”

“…Such lesions also alter the striatal gene expression of the g-aminobutyric acid (GABA)-synthesizing enzyme, glutamate decarboxylase (GAD), which exists as two isoforms of different molecular weight, GAD65 and GAD67. Thus, increases in GAD67 and/or GAD65 gene expression in the putamen and, to a lesser extent, in the caudate nucleus have been recently reported in MPTP-treated monkeys Soghomonian et al, 1994Soghomonian et al, , 1996. Increased striatal GAD67 gene expression has also been observed in rats with 6-hydroxydopamine (6-OHDA) lesions of dopamine neurons (Segovia et al, 1990;Soghomonian et al, 1992;Vernier et al, 1988).…”

Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

“…It is therefore most likely that the increased level of GAD protein in GPi represents increased activity of local axon collaterals of GPi neurons and is therefore another indicator that GPi activity is enhanced in MPTP-treated animals. This is also suggested by studies that have demonstrated that GAD mRNA levels in GPi are increased in parkinsonism Soghomonian et al, 1994;Herrero et al, 1996a;Salin et al, 2002;Schneider and Wade, 2003).…”

Targeting Group III Metabotropic Glutamate Receptors Produces Complex Behavioral Effects in Rodent Models of Parkinson's Disease

“…This hypothesis, which implies hypoactivity of the GP in PD state (Albin et al, 1989;DeLong, 1990), does not fit however with recent reconsideration of GP function in the BG circuitry (Levy et al, 1997). The expression of the GABA-synthesizing enzyme GAD67 is enhanced in the GP rather than decreased after extensive unilateral DA denervation (Kincaid et al, 1992;Soghomonian and Chesselet, 1992;Soghomonian et al, 1994;Nielsen and Soghomonian, 2003). In contrast, pallidal expression of cytochrome oxidase subunit I (COI), a metabolic index of neuronal activity, was not enhanced after partial DA denervation (Oueslati et al, 2005).…”