CD38 and Behavior: Moving from Correlation to Causality?

Abstract

m f w d o ( p C o a t I n this issue, Feldman et al. (1) demonstrate associations between plasma oxytocin (OT) levels and genetic variability in the OT pathway, implying that OT is responsible for parent/infant nteractions and confirming its role in bond formation in humans. urther evidence of early social influences on the system is that arental care received during infancy is paralleled by higher levels f plasma OT in adulthood. Neurogenetics suggests that these vents are associated with polymorphisms in the oxytocin receptor OXTR) and CD38 genes (1). Figure 1 shows a schematic representaion of the sequence leading from the secretion of OT by hypothaamic neurons to its uptake by OXTR, highlighting the key role layed by CD38. Some points are still unexplored. Here we focus on he points grounded in basic science, but conducted in human odels. CD38 transduces signals in leukocytes upon binding by CD31. D38 is also a nicotinamide adenine dinucleotide (and nicotinmide adenine dinucleotide phosphate)– consuming ectoenzyme, roducing cyclic adenosine diphosphate-ribose (cADPR) and denosine diphosphate-ribose (ADPR) as well as nicotinic acid adeine dinucleotide phosphate (NAADP). Cyclic adenosine diphoshate-ribose and nicotinic acid adenine dinucleotide phosphate re inositoltriphosphate–independent calcium-mobilizing moleules involved in hormone secretion (eg, insulin in human and OT in ice) (2,3). The finding that CD38 has multiple functions polarized he research community: immunological features were the focus in uman CD38, whereas the enzymatic functions were mostly studed in Cd38 murine models. Lacking a knockout model, the huan CD38 community worked prevalently on diseases. These had o be of unknown pathogenesis and chronic to allow the tracking of heir progression and outcome. The most studied model was hronic lymphocytic leukemia (2). When murine and human studies were gaining momentum, an stounding observation was made in Cd38 mice. Jin et al. (4) revealed hitherto unnoticed behavioral defects by investigating the interaction of Cd38 mice with their peers and offspring. The phenotype is consistent with a defect in short-term social memory, resulting in forgetfulness of their pups’ location and previous encounters with potential mates. Although Cd38 mice synthesize OT in the neurohypophysis, its release is impaired. Surprisingly, vasopressin is unaffected. A correction of the defect with a normal CD38 gene reverts the clinical phenotype, as does exogenous OT administration. Because of recent advances in knowledge about OT, the hormone is no longer considered restricted to parturition and lactation. A link has been drawn between OT and behavior in several otherwise unrelated studies. Among these, Insel and Young (5) found that the central expression of OXTR (and AVPR1A) is different in prairie and mountain male voles, whose mating habits are markedly different. Subsequent studies by empirical economists (Zurich, Switzerland) indicated that OT positively influences trust in human