Activation of PDE2A moderates pathologically high cAMP/PKA responses to dopamine in dyskinetic mice

Abstract

Dopamine depletion in Parkinson's disease (PD) leads to severe motor and cognitive disturbances. While L-DOPA replacement therapy efficiently alleviates the motor symptoms, it leads to long-term complications, notably dyskinesia. These deregulations are closely associated with an exacerbated cAMP/PKA signaling and alterations in striatal plasticity. In this study we used genetically encoded biosensors to monitor cAMP and PKA signals in the 6-OHDA mouse model of Parkinson's disease. In these mice cAMP levels and PKA signaling were markedly up-regulated. We observed that stimulation of the cGMP signaling by a NO donor, DEANO, efficiently down-regulated the amplitude of these hypersensitive responses and this regulatory effect was mediated by PDE2A. Indeed, the stimulation of PDE2A by cGMP was found to efficiently reduce the excessive cAMP/PKA signaling triggered by D₁ receptor stimulation, and this, despite unaltered PDE2A expression. These findings strongly suggest that boosting PDE2A activity in the striatum would be of therapeutic value to moderate the excessive cAMP/PKA responses and mitigate the long-term changes in striatal neurons associated with the adverse effects of L-DOPA treatment.