title: Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-32
abstract: Type 10A phosphodiesterase (PDE10A) is highly expressed in the striatum, in striatonigral and striatopallidal medium-sized spiny neurons (MSNs), which express D1 and D2 dopamine receptors, respectively. PDE10A inhibitors have pharmacological and behavioral effects suggesting an antipsychotic profile, but the cellular bases of these effects are unclear. We analyzed the effects of PDE10A inhibition in vivo by immunohistochemistry, and imaged cAMP, cAMP-dependent protein kinase A (PKA), and cGMP signals with biosensors in mouse brain slices. PDE10A inhibition in mouse striatal slices produced a steady-state increase in intracellular cAMP concentration in D1 and D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels. Surprisingly, the PKA-dependent AKAR3 phosphorylation signal was strong in D2 MSNs, whereas D1 MSNs remained unresponsive. This effect was also observed in adult mice in vivo since PDE10A inhibition increased phospho-histone H3 immunoreactivity selectively in D2 MSNs in the dorsomedial striatum. The PKA-dependent effects in D2 MSNs were prevented in brain slices and in vivo by mutation of the PKA-regulated phosphorylation site of 32 kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which is required for protein phosphatase-1 inhibition. These data highlight differences in the integration of the cAMP signal in D1 and D2 MSNs, resulting from stronger inhibition of protein phosphatase-1 by DARPP-32 in D2 MSNs than in D1 MSNs. This study shows that PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs.
authors.affiliation: CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Polito
authors.affiliation: CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.
authors.forename: Elvire
authors.initials: E
authors.lastname: Guiot
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle , Montpellier, F-34094, France ; Institut National de la Santé et de la Recherche Médicale, U661 , Montpellier, F-34094, France ; Universités de Montpellier 1 & 2, UMR-5203 , Montpellier, F-34094, France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gangarossa
authors.affiliation: Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France ; Institut National de la Santé et de la Recherche Médicale UMR-S 839 , Paris, France ; Institut du Fer à Moulin , Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Longueville
authors.affiliation: CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Doulazmi
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle , Montpellier, F-34094, France ; Institut National de la Santé et de la Recherche Médicale, U661 , Montpellier, F-34094, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
authors.affiliation: Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France ; Institut National de la Santé et de la Recherche Médicale UMR-S 839 , Paris, France ; Institut du Fer à Moulin , Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
authors.affiliation: Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France ; Institut National de la Santé et de la Recherche Médicale UMR-S 839 , Paris, France ; Institut du Fer à Moulin , Paris, France.
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
authors.affiliation: CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Paupardin-Tritsch
authors.affiliation: CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.
authors.forename: Liliana R V
authors.initials: LR
authors.lastname: Castro
authors.affiliation: CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vincent
keywords: biosensor imaging; cAMP; phosphodiesterase; protein kinase; schizophrenia; striatum