Activation of PDE2A moderates pathologically high cAMP/PKA responses to dopamine in dyskinetic mice
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 cA...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-08-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125001846 |
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| Summary: | 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. |
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| ISSN: | 1095-953X |