RT Journal Article SR Electronic T1 Selective effects of PDE10A inhibitors on striatopallidal neurons require phosphatase inhibition by DARPP-32 JF eneuro JO eneuro FD Society for Neuroscience SP ENEURO.0060-15.2015 DO 10.1523/ENEURO.0060-15.2015 A1 Marina Polito A1 Elvire Guiot A1 Giuseppe Gangarossa A1 Sophie Longueville A1 Mohamed Doulazmi A1 Emmanuel Valjent A1 Denis Hervé A1 Jean-Antoine Girault A1 Danièle Paupardin-Tritsch A1 Liliana R. V. Castro A1 Pierre Vincent YR 2015 UL http://www.eneuro.org/content/early/2015/08/25/ENEURO.0060-15.2015.abstract AB 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 (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 cAMP signal in D1 and D2 MSNs, resulting from stronger inhibition of protein phosphatase-1 by DARPP-32 in D2 MSNs, than in D1. This study shows that PDE10A inhibitors share with antipsychotics the property of activating preferentially PKA-dependent signaling in D2-MSNsSignificance Statement: The striatum is mainly composed of medium-sized spiny neurons that express either dopamine D1 receptors or dopamine D2 receptors. Their activity is associated with either initiation of movement or action suppression, respectively. Biosensor imaging revealed that pharmacological inhibition of type 10A phosphodiesterase increased cAMP in D1 and D2 neurons in the same manner, but only D2 neurons exhibited an increase in PKA-mediated phosphorylation level. This effect resulted from an asymetrical regulation of phosphatases by DARPP-32. D2 neurons are thus more prone to respond to a tonic cAMP signal than D1 neurons, a property, which may explain how phosphodiesterase 10A inhibitors produced antipsychotic-like behavioral effects. This D1/D2 imbalance may also be critical for reward-mediated learning and action selection.