Developmental regulation of glutamic acid decarboxylase mRNA expression and splicing in the rat striatum by dopamine

Dopamine (DA) promotes the morphological differentiation of striatal GABAer gic neurons through D-1 receptor activation and cAMP/PKA signaling. In this study, we investigated the developmental role of DA on the expression of t he two GAD,,,,, genes and the alternative splicing of GAD,, transcripts in the rat striatum. In vivo, embryonic and adult GAD,, splice variants and GA D,, transcripts increased until E17 and E19, respectively. Thereafter, the embryonic GAD,, isoform disappeared, whereas GAD,, mRNA levels remained unc hanged postnatally. The hypothesis that the prenatal ingrowth and functiona l maturation of nigrostriatal afferents may be responsible for these develo pmental events through DA-dependent signaling pathways was tested in E17 ra t striatal cultures. Treatment with DA and D-1 but not D-2 agonists decreas ed the ratio of embryonic to adult GAD(67) mRNAs and increased GAD(65) mRNA levels as well as GABA synthesis rates. Our findings demonstrate a distinc t developmental switch in the regulation of GAD,, expression and GAD(67) sp licing in the rat striatum which clearly depends upon D-1 receptor but not D-2 signaling. The dopaminergic input thus appears to control the functiona l differentiation of GABAergic neurons not only by ugregulation of expressi on of the two GAD genes but also by regulating GAD(67) splicing. (C) 2000 E lsevier Science B.V. All rights reserved.