DARPP-32 mediates serotonergic neurotransmission in the forebrain

Serotonin is implicated in the regulation of complex sensory, motor, affective, and cognitive functions. However, the biochemical mechanisms whereby this neurotransmitter exerts its actions remain largely unknown. DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of molecular weight 32,000) is a phosphoprotein that has primarily been characterized in relation to dopaminergic neurotransmission. Here we report that serotonin regulates DARPP-32 phosphorylation both in vitro and in vivo. Stimulation of 5-hydroxy-tryptamine (5-HT(4) and 5-HT(6)) receptors causes an increased phosphorylation state at Thr(34)–DARPP-32, the protein kinase A site, and a decreased phosphorylation state at Thr(75)–DARPP-32, the cyclin-dependent kinase 5 site. Furthermore, stimulation of 5-HT(2) receptors increases the phosphorylation state of Ser(137)–DARPP-32, the casein kinase-1 site. Behavioral and gene transcriptional effects induced by compounds that selectively release serotonin were greatly reduced in DARPP-32 knockout mice. Our data indicate that DARPP-32 is essential not only for dopaminergic but also for serotonergic neurotransmission.