Somato-axodendritic release of oxytocin into the brain due to calcium amplification is essential for social memory

Abstract

Oxytocin (OT) is released into the brain from the cell soma, axons, and dendrites of neurosecretory cells in the hypothalamus. Locally released OT can activate OT receptors, form inositol-1,4,5-trisphosphate and elevate intracellular free calcium (Ca2+) concentrations [(Ca2+)i] in self and neighboring neurons in the hypothalamus, resulting in further OT release: i.e., autocrine or paracrine systems of OT-induced OT release. CD38-dependent cyclic ADP-ribose (cADPR) is also involved in this autoregulation by elevating [Ca2+]i via Ca2+ mobilization through ryanodine receptors on intracellular Ca2+ pools that are sensitive to both Ca2+ and cADPR. In addition, it has recently been reported that heat stimulation and hyperthermia enhance [Ca2+]i increases by Ca2+ influx, probably through TRPM2 cation channels, suggesting that cADPR and TRPM2 molecules act as Ca2+ signal amplifiers. Thus, OT release is not simply due to depolarization–secretion coupling. Both of these molecules play critical roles not only during labor and milk ejection in reproductive females, but also during social behavior in daily life in both genders. This was clearly demonstrated in CD38 knockout mice in that social behavior was impaired by reduction of [Ca2+]i elevation and subsequent OT secretion. Evidence for the associations of CD38 with social behavior and psychiatric disorder is discussed, especially in subjects with autism spectrum disorder.

An immunohistochemical, enzymatic, and behavioral study of CD157/BST-1 as a neuroregulator

“…CD157 is a sister molecule of the CD38 cell-surface antigen with ADP-ribosyl cyclase activity [5, 6, 12], but the phenotypes of CD157 KO and CD38 KO mice are quite different [4, 9–11, 46]. The role of CD38 in OT secretion into the brain has been established [4, 9–11]; CD38 mediates cADPR production, TRMP2 and ERK1/2 activation, Ca 2+ -mobilization, and OT release [47] (Fig.…”

“…The role of CD38 in OT secretion into the brain has been established [4, 9–11]; CD38 mediates cADPR production, TRMP2 and ERK1/2 activation, Ca 2+ -mobilization, and OT release [47] (Fig. 8).…”

“…CD38, originally identified as playing a role in hematopoietic cells and leukocytes and in the pathogenesis of leukemia and HIV infection [5–8], has a critical role in oxytocin (OT) secretion in the hypothalamus and in the regulation of social memory and social interactions [4, 9, 10]. The mechanism underlying the regulation of OT release from oxytocinergic neurons involves increases in intracellular Ca 2+ concentrations by mobilization of Ca 2+ from ryanodine receptors [11–13] to intracellular Ca 2+ pools by cyclic ADP-ribose (cADPR). CD38, together with CD157, is a member of the ADP-ribosyl cyclase family, which catalyzes the formation of cADPR from β-NAD + [14, 15].…”

CD38, CD157, and RAGE as Molecular Determinants for Social Behavior

“…The role of CD38 in OT secretion into the brain is already established [9][10][11]21,22]. CD38 mediates multiple reactions such as ADPR and cADPR production, TRMP2 and extracellular signal-regulated kinase (ERK1/2) activation, Ca 2+ -mobilization, and OT release [68].…”

“…The first study to report physiological functions of CD38 in the brain was published by Jin et al in 2007, in that CD38 has an important role in oxytocin (OT) secretion in the hypothalamus and in regulating of social memory and social interactions [8][9][10]. The mechanism underlying the regulation of OT release from OT-containing neurons involves increases in intracellular free Ca 2+ concentrations by mobilization of Ca 2+ through ryanodine receptors type II or III [3,4,11,12] from intracellular Ca 2+ pools by cyclic ADP-ribose (cADPR).…”