Striatal signaling: two decades of progress

The striatum and its ventral extension the nucleus accumbens (NAcc) are the main inputs structure of the basal ganglia circuit (Figure 1). While the striatum appears to be essential for the selection and initiation of actions and for the learning of habits and skills, the NAcc seems to be more involved in motivation and reward. Interestingly, dysfunctional plasticity of these structures has been associated with prominent neurological and psychiatric disorders such as Parkinson’s disease, obsessive-compulsive disorder, Tourette’s syndrome, and drug addiction. The aims of this Special Topic was to propose a series of reviews covering our recent understanding on striatal signaling pathways, which are activated by a variety of therapeutic agents or drugs of abuse in physiological and pathological context. The 17 articles provide a deep overview of our current knowledge and highlight how recent advances in cell-type specific technologies, including fluorescent reporter mice, conditional knockout, and viral-mediated gene transfer allow to untangle the complexity of studying signal transduction in the brain in vivo. The content of each of these articles is briefly summarized below. The first article, by Nishi et al. (2011) summarizes some of the mechanisms involved in the modulation of dopamine D1R signaling. The authors review both the canonical and noncanonical D1R signaling cascade that coupled to Gαolf/adenylyl cyclase/PKA signaling and to Gq/phospholipase C or Src family kinase, respectively. They also extensively discuss the role played by Phosphodiesterases (PDEs) in the control of striatal signaling. In the second article, Hervé (2011) reviews the critical role of the highly specialized G-protein subunit heterotrimer containing Gαolf/β2/γ7 that couples D1R and A2aR to adenylyl cyclase 5. The physiological consequences of the alterations of Gαolf levels and/or activity are also extensively discussed. The third article by Perreault et al. (2011) reviews the current knowledge on D1R-D2R heteromers. Although, it is commonly accepted that D1R and D2R are preferentially expressed in striatonigral and striatopallidal MSNs, respectively, the authors put forward the hypothesis that MSNs co-expressing both receptors display unique signaling properties supporting the existence of a “novel third pathway”. Ferré et al. (2011) focus on the role of the different subpopulation of striatal adenosine A2aR. Postsynaptically, A2aR are localized in striatopallidal MSNs where they form heteromers with dopamine D2R, cannabinoid CB1R, andmGluR5R. The authors also highlight how presynaptic A2aRA1R heteromers can impact on striatal signaling. After a brief overview of the major G-protein-coupled receptors (GPCRs) and their downstream effectors, Xie and Martemyanov (2011) discuss the progress made in understanding the roles of RGS proteins in controlling striatal G-protein signaling. A particular attention has been paid on the role of the striatal-enriched RGS9-2 protein on dopamine and opioid signaling. The sixth article by Del’Guidice et al. (2011) deals with the role of β-arrestin 2 on the regulation of dopamine receptor desensitization as well as the involvement of this scaffoling protein in the control of the Akt/GSK3 signaling pathways. Potential molecular targets of β-arrestin 2/Akt/GSK3 signaling are also reviewed. After an outline of the current knowledge of the signaling cascades that target the nucleus, Matamales and Girault (2011) describe how through the regulation of protein kinases, phosphatases, and transport through the nuclear pore, a signal initiated at the plasmamembrane is amplified in the cytosol and then relayed to the nucleus. Identified mechanisms involved in transcription regulation and chromatin re-modeling in MSNs are also discussed. In the eighth article Walaas et al. (2011) provide a comprehensive review on the regulation and roles of the three major subclasses of serine/threonine protein phosphatases, PP1, PP2B, and PP2A. Their direct or indirect regulation by the striatum-enriched phosphoproteins DARPP32, RCS, and ARPP-16 is extensively discussed. The ninth article by Fitzpatrick and Lombroso (2011) also deals with the role of protein phosphatases focusing more specifically on the striatalenriched protein tyrosine phosphatase (STEP). The structure and the regulation of STEP phosphorylation are described, as are the functional consequences of STEP dysfunctions in various neurological and neuropsychiatric disorders. The dysregulation of striatal signaling induced by the drugs of abuse leads to an abnormal neuronal plasticity that under normal circumstances serves to shape appropriate reward-related behaviors. After a rapid update on the role played by dopamine receptors in drug addiction, Philibin et al. (2011) perform an in-depth review of intracellular signaling cascades, involving specific kinases and phosphatases affected by cAMP and Ca2+ that modulate neuroplasticity to affect behavioral outcome. Particular emphasis is placed on PKA, cdk5, ERK, CamKII, and PKC. Glutamate receptors cooperate closely with dopamine to regulate striatal signaling. In the article of Mao et al. (2011) several major types of post-translational modifications of glutamate receptors, including phosphorylation, palmitoylation, ubiquitination, and sumoylation are discussed. The impact of such modifications on striatal signaling and drug-induced neuronal plasticity is also addressed. The article by Lobo and Nestler (2011) discuss extensively how recent advances in cell-type-specific technologies have advanced the field toward a more comprehensive understanding