Social memory, amnesia, and autism: Brain oxytocin secretion is regulated by NAD+ metabolites and single nucleotide polymorphisms of CD38

Abstract

Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. The autism spectrum disorders (ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. However, the etiology of ASDs remains largely unknown. Therefore, the theoretical basis for pharmacological treatments has not been established. Hence, there is a rationale for investigating single nucleotide polymorphisms (SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 (C > A) was associated with high-functioning autism (HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C > T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W; R140W) in CD38. This mutation was found in 4 probands of ASD and in family members of 3 pedigrees with variable levels of ASD or ASD traits.The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. The OXT levels were unchanged in healthy subjects with or without this mutation. One proband with the R140W allele receiving intranasal OXT for approximately 3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and 3 aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods; three subjects showed improved symptoms, while 2 showed little or no effect. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials.

Visual attention for social information and salivary oxytocin levels in preschool children with autism spectrum disorders: an eye-tracking study

“…Individuals with ASD have particular difficulty in interpreting nonverbal social information such as facial expressions, vocal expressions (Doi et al, 2013), pointing gestures (Paparella et al, 2011), and body gestures (Centelles et al, 2012) that lead to severe social impairment (Hill and Frith, 2003). Recently, many studies have revealed relations between OT and social functioning (e.g., Munesue et al, 2010; Higashida et al, 2012), and have devoted particular attention to OT as a candidate treatment for social impairments in patients with ASD. In fact, plasma OT levels in patients with ASDs are reportedly low (Modahl et al, 1998).…”

Acetylcholine-Induced M/KCNQ Current Inhibition is Regulated by CD38 and A-Kinase Anchoring Protein in Neuroblastoma Cells

“…In conclusion, it is clear that CD38 plays pivotal roles under neuronal physiological as well as pathophysiological conditions (Malavasi et al, 2008;Rah et al, 2012;Higashida, et al, 2012aAkimoto et al, 2013). DNA manipulation of CD38 and cADPR in the mAChR-signal cascade in NG108-15 cells revealed that CD38 has great impact on M-current inhibition.…”

Neurobiological Aspects of Face Recognition: The Role of Oxytocin

“…Being actually NAD + -glycohydrolase, CD38 synthesizes cyclic ADP-ribose which is a Ca 2+ -mobilizing second messenger present in OT-producing neurons (Jin et al, 2007). Therefore, researchers have postulated that impaired CD38-mediated OT release might be caused by intracellualar NAD + depletion (i.e., under conditions of oxidative stress or DNA damage and hyperactivation of NAD + -consuming DNA repair enzymes), and diminished CD38 expression or lower enzymatic activity may lead to prominent alterations in various aspects of mammalian social behavior (Jin et al, 2007; Higashida et al, 2012; Lopatina et al, 2012). Low CD38 expression is associated with a risk for ASD through impaired OT secretion (Lerer et al, 2010).…”