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.

Abstract

The levels of mRNAs encoding for the two isoforms of glutamate decarboxylase, GAD65 and GAD67, were measured in subpopulations of striatal neurons in adult rats depleted of dopamine as neonates with 6-OHDA and chronically injected with vehicle or with the dopamine receptor agonists apomorphine or SKF-38393. In adult rats depleted of dopamine as neonates, an increase of GAD65 and GAD67 mRNA levels was measured in the striatum. These changes were paralleled by an increase in preproenkephalin (PPE) and a decrease in preprodynorphin (PPD) mRNA levels. Quantitative analysis at the cellular level indicated that GAD67 mRNA levels were increased in PPE-labeled neurons, whereas GAD65 mRNA levels were increased in PPE-unlabeled neurons. Chronic and systemic injections of apomorphine or SKF-38393 induced further increases in striatal GAD65 and GAD67 mRNA levels. These increases were only detected in the subpopulation of PPE-unlabeled neurons and were paralleled by an increase in PPD mRNA levels. The increases in GAD67, GAD65, and PPD mRNA levels induced by SKF-38393 were abolished by the administration of the D1 receptor antagonist SCH-23390. The present results provide further evidence that GAD67 and GAD65 gene expression is differentially regulated in the two subpopulations of efferent striatal neurons. They also suggest that neonatal depletions in dopamine levels induce alterations of GABA-mediated signaling in the two subpopulations of striatal efferent neurons. We speculate that these alterations are involved in the behavioral particularities exhibited by rats depleted of dopamine as neonates.