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

Abstract

Dopamine (DA) promotes the morphological differentiation of striatal GABAergic neurons through D 1 receptor activation and cAMP/PKA signaling. In this study, we investigated the developmental role of DA on the expression of the two GAD 65/67 genes and the alternative splicing of GAD 67 transcripts in the rat striatum. In vivo, embryonic and adult GAD 67 splice variants and GAD 65 transcripts increased until E17 and E19, respectively. Thereafter, the embryonic GAD 67 isoform disappeared, whereas GAD 65 mRNA levels remained unchanged postnatally. The hypothesis that the prenatal ingrowth and functional maturation of nigrostriatal afferents may be responsible for these developmental events through DA-dependent signaling pathways was tested in E17 rat striatal cultures. Treatment with DA and D 1 but not D 2 agonists decreased 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 distinct developmental switch in the regulation of GAD 65 expression and GAD 67 splicing in the rat striatum which clearly depends upon D 1 receptor but not D 2 signaling. The dopaminergic input thus appears to control the functional differentiation of GABAergic neurons not only by upregulation of expression of the two GAD genes but also by regulating GAD 67 splicing.