CALCIUM AND CAMP INTERPLAYS DURING NEURONAL PLASTICITY <EM>IN VITRO</EM>

Neurons transfer information via synapses, where synaptic plasticity occurs by modulating synaptic transmission. Synaptic plasticity is essential for learning and memory. It includes Long-Term Potentiation (LTP), enhancing transmission efficacy, and Long-Term Depression (LTD), decreasing it. These processes involve N-Methyl-D-Aspartate receptors (NMDAR). Glutamate activates NMDAR, triggering intracellular calcium influx and activating effectors such as CaM kinase. Besides calcium, cyclic nucleotide monophosphates (cNMPs) also modulate the efficacy of synaptic transmission. cAMP is produced by adenylyl cyclase (AC). cGMP is produced by guanylyl cyclase activation. cNMPs signal through kinases (PKA, PKG) and possibly downstream MAPK to induce LTP and LTD. Calcium can regulate cAMP during synaptic plasticity establishment by either reinforcing cAMP production through calcium-sensitive cyclases 1 and 8 or, conversely, by phosphodiesterase 1 (PDE1) activation, which is responsible for cAMP degradation. Calcium also activates nitric oxide synthases, thus producing cGMP.Identical signaling pathways lead to opposite directions of plasticity. The precise interplay of these pathways in synaptic plasticity remains poorly understood. We hypothesize that neurons differentiate LTD and LTP signals through spatio-temporal interconnection of these signaling pathways. The aim of the study is to characterize the spatio-temporal dynamics of these secondary messengers using FRET and BRET biosensors during synaptic plasticity protocols.Our results show that NMDA application inducing LTP or LTD induces cAMP and cGMP production. LTP stimulation alters neuronal responsiveness to subsequent stimuli. Inhibition of cGMP-activated PDE2 partially recovers neuronal responsiveness. These results suggest that calcium and cNMPs interact during synaptic plasticity, leading to different states in LTP and LTD protocols.