A phosphatase cascade by which rewarding stimuli control nucleosomal response

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Abstract
Disruptions in dopamine signalling have been implicated in psychiatric disorders, such as schizophrenia and drug addiction. The phosphoprotein DARPP-32 is a prominent mediator of dopamine signalling in the striatum, a part of the brain where dopaminergic activation has been linked to reward and learning. Now a novel signal transduction cascade involving nuclear accumulation of DARPP-32 has been discovered, induced by both drugs of abuse and natural stimuli such as food. Disruption of this cascade alters the behavioural effects of the drugs and decreases motivation for food, suggesting a role for this mechanism in the in vivo actions of dopamine signalling. Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.