BBB seminar: Pierre Vincent
Monitoring the integration of cyclic nucleotide signals in neurons using biosensor imaging
Cellular Integration of Neuromodulatory Processes, UMR8256 Biological Adaptation and Ageing, Sorbonne Universities, UPMC University Paris, France
In neurons, cyclic nucleotides (mainly cAMP and cGMP) are intracellular second messengers which integrate the response to various neuromodulatory signals. Cyclic nucleotides are degraded by several types of phosphodiesterases, and inhibitors of phosphodiesterases are actively studied as possible therapeutic targets to treat neuropsychiatric diseases. We imaged genetically-encoded FRET biosensors in brain slice preparations to study neuromodulation and analyze the functional role played by specific phosphodiesterases in the regulation of cyclic nucleotide signaling.
In the striatum, candidate drugs which target the type 10 phosphodiesterase revealed an unexpected dissymmetrical mechanism of cAMP/PKA signal integration in the two types of medium spiny neurons, an imbalance which depends on DARPP-32 (32-kDa dopamine- and cAMP-regulated phosphoprotein). Type 1 phosphodiesterase, which is activated by calcium-calmodulin and therefore links neuronal activity with cyclic nucleotide signaling, appears to be functionally present in the cortex, hippocampus and striatum. Finally, since dopamine plays a central role in contextual learning, we compared the response to dopamine in the two types of spiny neurons present in the striatum: while most theories on learning processes in the basal ganglia assume a large difference in affinity between D1 and D2 receptors, our data show that dopamine has a similar efficacy on cAMP signaling, while downstream signal integration provides a striking difference in cell responsiveness to phasic dopamine.
Chairperson: Clive R. Bramham, Department of Biomedicine