Cross-pathway integration of cAMP signals through cGMP and calcium-regulated phosphodiesterases in mouse striatal cholinergic interneurons.

Background and purpose: Acetylcholine plays a key role in striatal function. Firing properties of striatal cholinergic interneurons depend on intracellular cAMP through the regulation of I_h currents. Yet, the dynamics of cyclic nucleotide signalling in these neurons have remained elusive.

Experimental approach: We used highly selective FRET biosensors and pharmacological compounds to analyse the functional contribution of phosphodiesterases in striatal cholinergic interneurons in mouse brain slices.

Key results: PDE1A, PDE3A and PDE4 appear as the main controllers of cAMP levels in striatal cholinergic interneurons. The calcium signal elicited through NMDA or metabotropic glutamate receptors activates PDE1A, which degrades both cAMP and cGMP. Interestingly, the nitric oxide/cGMP pathway amplifies cAMP signalling via PDE3A inhibition-a mechanism hitherto unexplored in a neuronal context.

Conclusions and implications: The expression pattern of specific PDE enzymes in striatal cholinergic interneurons, by integrating diverse intracellular pathways, can adjust cAMP responses bidirectionally. These properties eventually allow striatal cholinergic interneurons to dynamically regulate their overall activity and modulate acetylcholine release. Remarkably, this effect is the opposite of the cGMP-induced inhibition of cAMP signals involving PDE2A in striatal medium-sized spiny neurons, which provides important insights for the understanding of signal integration in the striatum.