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.

Gene expression of the GAD67 and GAD65 isoforms of glutamate decarboxylase is differentially altered in subpopulations of striatal neurons in adult rats lesioned with 6-OHDA as neonates

“…In the present study, we show that this increase occurs in neurons that express PPE, which have been shown to be striatopallidal neurons (Gerfen and Young, 1988). Increases in striatal GAD67 mRNA levels have also been observed in PPE-labeled neurons of rats or monkeys depleted of dopamine as adults Soghomonian and Laprade, 1997;unpublished observations). In monkeys, GAD65 mRNA levels are also increased in PPE-labeled striatopallidal neurons .…”

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.…”

Pathophysiology of Parkinsonism

“…Changes in GABAergic transmission have also been evaluated with measurements of mRNA or protein levels for the GABA-synthesizing enzyme glutamate decarboxylase (GAD), under the assumption that GAD levels reflect the activity of GABAergic pathways. In striatopallidal projection neurons and in GPi and SNr cells there is a selective increase in GAD mRNA in dopamine-depleted animals (Kincaid et al, 1992, Laprade and Soghomonian, 1999, Salin et al, 2002, Soghomonian and Laprade, 1997. However, in GPe and STN, the level of GAD is unchanged (Pedneault and Soghomonian, 1994, Schneider and Wade, 2003, Soares et al, 2004, contrary to what the rate model would predict.…”