Characterization of CNP-induced cGMP signaling in the murine hippocampus

C-type natriuretic peptide (CNP) induced cGMP signaling is mediated by particulate guanylyl cyclase B (GC-B) and regulates endochondral ossification, oocyte maturation and sensory axon bifurcation. In contrast to cGMP produced by nitric oxide-activated guanylyl cyclase, not much is known about the role of CNP-induced cGMP signaling in the central nervous system. Therefore, we used the lacZ reporter mouse lines we developed to investigate the expression pattern of CNP and GC-B in the brain. Thereby, we detected a joint distribution of the ligand-receptor pair in the dentate granule neurons (DGNs) of the hippocampus, a brain structure involved in memory formation and adult neurogenesis. Additionally, CNP expression was observed in pyramidal neurons of the CA1-CA3 region and in some hilar cells. Biochemical analysis of hippocampal tissue extracts showed an increase in cGMP levels after CNP administration. Real-time FRET measurements of cGMP in DGNs expressing a genetically encoded cGMP sensor also showed robust cGMP generation in response to CNP as well as nitric oxide, suggesting the presence of both types of cGMP generators in DGNs. While analyzing specific phosphodiesterase (PDE) inhibitors, we found that PDE2A, similar to sensory neurons, is involved in modulating CNP-induced cGMP signaling in DGNs. Finally, we investigated the functional effects of CNP-induced cGMP generation in DGNs and observed an increase in neurite length, suggesting enhanced neuronal growth and plasticity. Our results provide new insights into cGMP signaling that may not only have implications for understanding hippocampal functions but also highlight potential avenues for therapeutic augmentation of cGMP signaling.