Like Joan Crawford in Mommie Dearest, some mutant mice can be terrible mothers. For example, mice lacking oxytocin receptors show deficits in maternal and social behaviors. Now Jin et al. report that the immune regulator CD38 mediates maternal and social behaviors by regulating oxytocin release in a recent article in Nature.
CD38 expression in immune cells is important in chemotaxis to sites of infection. However, CD38 also localizes to the brain. Like other 'ectoenzymes', CD38 localizes to the cell surface, with its catalytic domain positioned outside of the cell. CD38 hydrolyzes nicotinamide adenine dinucleotide (NAD+) to cyclic ADP ribose (known as cADPR), which acts at ryanodine receptors to release calcium from internal stores.
The authors tested the behavior of CD38 knockout mice. They showed normal anxiety and fear behaviors, but female knockout mice showed deficits in maternal behavior. After a 10-minute separation, wild-type mothers retrieved their scattered pups quickly and crouched over them to nurse. CD38 knockout mice took longer to retrieve their pups and crouched over them for a shorter period of time than did wild-type mice. Male knockout mice showed deficits in social recognition behaviors. Wild-type males investigated new female mice for a long time, but spent increasingly less time with familiar females. In contrast, CD38 knockout mice spent the same length of time investigating new and familiar females.
Deficits in oxytocin cause abnormal social behaviors in CD38 knockout mice. Neurons in the supraoptic and paraventricular hypothalamic nuclei make oxytocin and vasopressin, which are released into the bloodstream at the hypothalamic axon terminals that make up the posterior pituitary. The authors found reduced levels of oxytocin but similar levels of vasopressin in the plasma of CD38 knockout relative to wild-type mice. In contrast, they found increased levels of oxytocin in the hypothalamus and posterior pituitary of CD38 knockout relative to wild-type mice. A single injection of oxytocin rescued wild-type maternal and social recognition behaviors in female and male CD38 knockouts, respectively. Hypothalamic cells and pituitary terminals showed reduced depolarization-induced oxytocin release in CD38 knockout relative to wild-type mice. Therefore, stimulus-induced oxytocin release was impaired in CD38 knockout mice.
How does CD38 mediate oxytocin release? Depolarization induced a smaller rise in intracellular calcium concentration in hypothalamic cells from CD38 knockout relative to wild-type mice. Relative to wild-type mice, CD38 knockout mice showed reduced CD38 enzymatic activity in the hypothalamus and reduced levels of cADPR in the hypothalamus and posterior pituitary. CD38 knockout hypothalamic nerve terminals treated with cADPR and digitonin (to permeabilize cell membranes) showed stimulus-induced oxytocin release similar to wild-type mice. Therefore, CD38's enzymatic activity is necessary in the calcium-induced release of oxytocin.
Because children with autistic spectrum disorders show reduced plasma levels of oxytocin, the authors hypothesize that CD38 polymorphisms might contribute to autism.