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

Abstract

The cellular distribution of the mRNAs encoding for the two isoforms of glutamate decarboxylase, GAD67 and GAD65, was analyzed by in situ hybridization histochemistry in the caudate nucleus and putamen of control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian squirrel monkeys. On brain sections processed with a radioactive and a digoxigenin-labeled cRNA probe, the GAD67 and GAD65 mRNAs were colocalized in virtually all labeled neurons of the caudate nucleus and putamen, in both control and MPTP-treated monkeys. Furthermore, neurons labeled with the GAD cRNAs constituted at least 90% of all striatal neurons, as estimated on adjacent Nissl-stained sections. In the two groups of monkeys, double-labeling experiments using a combination of radioactive GAD67 or GAD65 and digoxigenin-labeled preproenkephalin (PPE) cRNA probes showed that roughly half of all neurons labeled with the GAD cRNAs were also labeled with the PPE cRNA probe. When compared to controls, GAD67 and GAD65 mRNA levels were higher in the putamen, and to a lesser extent in the caudate nucleus, of MPTP-treated monkeys. Further analysis of labeling at the cellular level in a dorsolateral sector of the putamen revealed that GAD67 and GAD65 mRNA levels in MPTP-treated monkeys were increased in PPE-labeled (presumed striato-pallidal) neurons but not in PPE-unlabeled (presumed striato-nigral) neurons. Our results demonstrate that most neurons in the caudate nucleus and putamen of squirrel monkeys contain the mRNAs encoding for the two GAD isoforms. In addition, the selective increase in GAD mRNA levels in PPE-labeled neurons provides further evidence that striato-pallidal GABAergic neurons are hyperactive in MPTP-treated parkinsonian monkeys.

Recurrent Collateral Connections of Striatal Medium Spiny Neurons Are Disrupted in Models of Parkinson's Disease

“…This was not expected. Anatomical studies of 6-OHDAlesioned rats revealed that striatal expression of GAD (glutamate decarboxylase), the synthetic enzyme for GABA, rises (Soghomonian and Laprade, 1997). Moreover, the terminals of striatopallidal D 2 MSNs in the GPe and the striatum are enlarged, in parallel with an increased expression of the releasable peptide enkephalin (Ingham et al, 1991(Ingham et al, , 1997.…”

Striatal Preproenkephalin Gene Expression Is Upregulated in Acute but Not Chronic Parkinsonian Monkeys: Implications for the Contribution of the Indirect Striatopallidal Circuit to Parkinsonian Symptomatology

“…The extent to which GABA neurotransmission is upregulated in the indirect striatopallidal circuit in chronic symptomatic parkinsonian monkeys is unknown. However, GAD65 and GAD67 mRNA levels were increased in the dorsolateral putamen in acute parkinsonian monkeys (Soghomonian and Laprade, 1997). In these animals, GAD mRNA levels were increased in PPE-labeled (presumably striatopallidal) neurons but not in PPE-unlabeled neurons.…”

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

“…As mentioned above, based on electrophysiological and microdialysis findings, the activity of GPe neurons and, thus, of the GPe-GPi projection is reduced in parkinsonism. Based on measurements of striatal GAD mRNA levels, it is also known that striatal neurons projecting to GPi are not overactive in MPTP-treated monkeys (Soghomonian and Laprade, 1997). 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.…”