CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules and triggers proliferation and immune responses in lymphocytes. However, its role in the neuroendocrine system is unknown. In this study, we showed that adult CD38 knockout (CD38-/-) female and male mice have marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. As similar defects in maternal nurturing was reported in oxytocin (OT)-receptor-deficient mice, we measured the plasma level of oxytocin and vasopressin. The plasma concentration of oxytocin, but not vasopressin, was markedly low in CD38-/- mice. Subcutaneous injection of OT or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Electron microscopic analysis of the neurohypophysis showed that synthesis and vesicular packaging of OT is unaffected, but that OT secretion is (but not AVP secretion) is selectively and severely impaired in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results indicate that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders. (Nature 446: 41-45, 2007)
*Kanazawa University 21st Century COE Program on Innovative Brain Science on Development, Learning and Memory
