Cellular context shapes cyclic nucleotide signaling in neurons through multiple levels of integration.

Intracellular signaling with cyclic nucleotides are ubiquitous signaling pathways, yet the dynamics of these signals profoundly differ in different cell types. Biosensor imaging experiments, by providing direct measurements in intact cellular environment, reveal which receptors are activated by neuromodulators and how the coincidence of different neuromodulators is integrated at various levels in the signaling cascade. Phosphodiesterases appear as one important determinant of cross-talk between different signaling pathways. Finally, analysis of signal dynamics reveal that striatal medium-sized spiny neuron obey a different logic than other brain regions such as cortex, probably in relation with the function of this brain region which efficiently detects transient dopamine.

Pivotal role of phosphodiesterase 10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones.

BACKGROUND AND PURPOSE: Dopamine in the striatum plays a crucial role in reward processes and action selection. Dopamine signals are transduced by D1 and D2 dopamine receptors which trigger mirror effects through the cAMP/PKA signalling cascade in D1 and D2 medium-sized spiny neurons (MSNs). Phosphodiesterases (PDEs), which determine the profile of cAMP signals, are highly expressed in MSNs, but their respective roles in dopamine signal integration remain poorly understood. EXPERIMENTAL APPROACH: We used genetically encoded FRET biosensors to monitor at the single cell level the functional contribution of PDE2A, PDE4 and PDE10A in the changes of the cAMP/PKA response to transient and continuous dopamine in mouse striatal brain slices. KEY RESULTS: We found that PDE2A, PDE4 and PDE10A operate on the moderate to high cAMP levels elicited by D1 or A2A receptor stimulation. In contrast, only PDE10A is able to reduce cAMP down to baseline in both type of neurones, leading to the dephosphorylation of PKA substrates. CONCLUSION AND IMPLICATIONS: In both MSN types, PDE10A inhibition blunts the responsiveness to dopamine, whereas PDE2A or PDE4 inhibition reinforces dopamine action.