A phosphatase cascade by which rewarding stimuli control nucleosomal response

Abstract

SummaryDopamine orchestrates motor behavior and reward-driven learning. Perturbations of dopamine signaling 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 natural reinforcement learning, promote the nuclear accumulation of dopamine-and cAMPregulated phosphoprotein Mr=32,000 . This accumulation is mediated through a signaling 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 phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser-97 profoundly alters behavioral effects of drugs of abuse, and decreases motivation for food, underlining the functional importance of this signaling cascade.Midbrain dopamine (DA) neurons, activated following unexpected rewarding stimuli, are essential in reinforcement learning 1 . Drugs of abuse mimic the physiological action of DA neurons by increasing their firing rate or preventing DA uptake. Thus, they enhance extracellular DA levels in the forebrain, especially in the nucleus accumbens (NAc), a key structure required for the reinforcing effects of addictive drugs [2][3][4] . To understand how DA mediates reward-controlled learning, it is necessary to identify the intracellular events that trigger gene transcription alterations supporting long-lasting synaptic changes [5][6][7] . DARPP-32 (dopamine-and cAMP-regulated phosphoprotein, Mr=32,000) 8 is a prominent mediator of DA NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript signaling in the striatum 9 . DARPP-32 is highly enriched in striatal GABAergic mediumsize spiny neurons (MSN) 10 . Following activation of DA D1 receptors (D1R), DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) at Thr-34 and converted into a potent inhibitor of the multifunctional serine/threonine protein phosphatase-1 (PP1) 11 . DARPP-32-mediated inhibition of PP1 increases the phosphorylation of neurotransmitter receptors and ion channels crucial for synaptic function and plasticity 9 . DARPP-32 also regulates nuclear events, as demonstrated by alterations of drug-induced gene expression in mice lacking DARPP-32 or bearing a point mutation of 13 . Part of the control exerted by DARPP-32 on transcription is mediated by activation of the ERK pathway, dependent on the concomitant stimulation of D1R and glutamate NMDA receptors 13,14 . However, the precise mechanisms of information transfer from the cytoplasm to the nucleus of striatal neurons are still poorly characterized. Drugs of abuse and reinforcement learning trigger nuclear accumulation of DARPP-32 in striatal neuronsDARPP-32 has been extensively characterized as a cytoplasmic...

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

“…We, however, confirmed that cocaine administration increased phosphorylation of histone H3 at Ser10 (po0.05, Figure 4a) (Brami-Cherrier et al, 2005;Kumar et al, 2005;Stipanovich et al, 2008). This increase in H3 phosphorylation was also probably responsible for the increase in H3 phosphoacetylation observed after cocaine administration (Brami-Cherrier et al, 2005;Kumar et al, 2005;Stipanovich et al, 2008). Similar results (Figure 4b) were obtained in response to higher doses of morphine (60 mg/kg), ethanol (6 g/kg i.p.…”

“…Although the administration of sodium butyrate increased bulk histone aceylation in a dose-dependent manner (Supplementary Figure S1), we found that neither of the three drugs had a significant effect on bulk histone acetylation levels. We, however, confirmed that cocaine administration increased phosphorylation of histone H3 at Ser10 (po0.05, Figure 4a) (Brami-Cherrier et al, 2005;Kumar et al, 2005;Stipanovich et al, 2008). This increase in H3 phosphorylation was also probably responsible for the increase in H3 phosphoacetylation observed after cocaine administration (Brami-Cherrier et al, 2005;Kumar et al, 2005;Stipanovich et al, 2008).…”

Un nouveau mécanisme par lequel la récompense et les drogues modifient la chromatine dans les neurones

“…NAcc DA induite par la dopamine qui permet ce transfert et qui, en régulant la phosphorylation des histones, participe aux modifications du comportement induites par les récompenses physiologiques ou les drogues [5].…”

“…On pensait que cette régulation nucléaire était indirecte, notamment en raison du rôle exercé par la DARPP-32 sur l'activation de la voie des MAP kinases par les drogues [10]. Cependant, en examinant des coupes de cerveaux d'animaux traités par la cocaïne, l'amphétamine ou la morphine, nous avons observé une accumulation de DARPP-32 dans le noyau de certains neurones striataux, suggérant que la DARPP-32 pourrait avoir une fonction directe, encore insoupçonnée, dans le noyau [5]. Une accumulation similaire est aussi observée chez des souris qui apprennent à mettre leur museau dans un trou pour obtenir une boulette de nourriture, mais pas chez les animaux recevant la nourriture sans avoir travaillé pour cela.…”

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

“…For example, Aurora kinases A and B have been demonstrated to catalyze the addition of phosphate groups at H3S10, whereas mitogen-activated protein (MAP) kinase phosphatase-1 has previously been shown to promote the enzymatic removal of phosphate groups at this residue (Pascreau et al, 2003;Kinney et al, 2009). In brain, the dopamine and cAMP regulated protein phosphatase inhibitor, DARPP-32, as well as the MAP kinase, MSK1, provide excellent examples of enzymes regulating H3S10p in response to environmental stimuli, indicating histone phosphorylation as an important regulator of adult neuronal function (Brami-Cherrier et al, 2005;Stipanovich et al, 2008).…”