Essential role of the mitochondrial Na+/Ca2+exchanger NCLX in mediating PDE2-dependent neuronal survival and learning

Impaired phosphodiesterase (PDE) function and mitochondrial Ca2+ (i.e., [Ca2+]m) lead to multiple health syndromes by an unknown pathway. Here, we fluorescently monitor robust [Ca2+]m efflux mediated by the mitochondrial Na+/Ca2+ exchanger NCLX in hippocampal neurons sequentially evoked by caffeine and depo-larization. Surprisingly, neuronal depolarization-induced Ca2+ transients alone fail to evoke strong [Ca2+]m efflux in wild-type (WT) neurons. However, pre-treatment with the selective PDE2 inhibitor Bay 60-7550 effec-tively rescues [Ca2+]m efflux similarly to caffeine. Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site. We find that the protection of neurons against excito-toxic insults, conferred by PDE2 inhibition in WT neurons, is NCLX dependent. Finally, the administration of Bay 60-7550 enhances new object recognition in WT, but not in NCLX knockout (KO), mice. Our results iden-tify a link between PDE and [Ca2+]m signaling that may provide effective therapy for cognitive and ischemic syndromes.

Automated summary

We have discovered a link between PDE and mitochondrial calcium signaling, and found that selective PDE2 inhibitor can effectively rescue the efflux of calcium ions from mitochondria in neurons. Our results also demonstrate that the protective effect of PDE2 inhibition against excitotoxicity relies on the presence of NCLX. Additionally, the administration of the PDE2 inhibitor enhances new object recognition in mice.