34 These authors contributed equally to the work.Key Words: CD38, oxytocin, mutation, polymorphism, autism, high-functioning autism Author information Correspondence and requests for materials should be addressed to H. Higashida (haruhiro@med.kanazawa-u.ac.jp). 3 ABSTRACTThe neurobiological basis of autism spectrum disorder (ASD) remains poorly understood.Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons.In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p<0.040) and rs3796863 (p<0.005) showed significant associations with a subset of ASD (IQ>70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6%-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD.4

Oxytocin (OT) and arginine vasopressin (AVP) are neurohypophysial hormones. CD38 and cyclic ADP-ribose (cADPR) formation have been identified in the hypothalamus and are critical for OT, but not AVP, secretion, with profound consequential changes in social behaviors in mice. In the present study, we examined the immunolocalization of CD38, OT and AVP in different cell types in the hypothalamus and pituitary lobe of male mice. In the hypothalamus, CD38 immunoreactivity was found more commonly in OT neurons than AVP neurons. In the posterior pituitary lobe, the expression of CD38 was partly merged with OT and AVP, while pituicyte-like staining was also observed. In the CD38-deficient hypothalamus and posterior lobe, stronger staining of OT was observed, suggesting accumulation of OT due to lack of the releasing process, as reported previously. Co-expression of CD38 with glial cells showed that CD38 was rarely expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes. However, expression of CD38 protein in microglia was detected and more expression of CD38 in microglia was observed in the lipopolysaccharide-injected mouse brain. The expression of CD38 in different cell types, especially in microglia, in the hypothalamus and pituitary may indicate functional roles of CD38 in brain's immune system as well as in neurohypophysial hormone release.

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