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Nature 446, 41-45 (1 March 2007) | doi:10.1038/nature05526; Received 18 October 2006; Accepted 11 December 2006; Published online 7 February 2007

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CD38 is critical for social behaviour by regulating oxytocin secretion

Duo Jin1,2,18, Hong-Xiang Liu1,2,18, Hirokazu Hirai1,5,6,18, Takashi Torashima4,5, Taku Nagai7, Olga Lopatina1,2, Natalia A. Shnayder1,2, Kiyofumi Yamada1,7, Mami Noda9, Toshihiro Seike9, Kyota Fujita9, Shin Takasawa10, Shigeru Yokoyama1,2, Keita Koizumi1,2,5, Yoshitake Shiraishi3, Shigenori Tanaka3, Minako Hashii2, Toru Yoshihara1,5, Kazuhiro Higashida2, Mohammad Saharul Islam1,2, Nobuaki Yamada1,5, Kenshi Hayashi2,12, Naoya Noguchi10, Ichiro Kato14, Hiroshi Okamoto11, Akihiro Matsushima15, Alla Salmina16, Toshio Munesue13, Nobuaki Shimizu8, Sumiko Mochida17, Masahide Asano1,5 & Haruhiro Higashida1,2,4

  1. Kanazawa University 21st Century COE Program on Innovative Brain Science on Development, Learning and Memory, Kanazawa 920-8640, Japan
  2. Department of Biophysical Genetics, and,
  3. Department of Anatomy, and,
  4. Department of Cellular Neurophysiology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan
  5. Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan
  6. SORST, Japan Science and Technology Agency (JST), Kanazawa 920-8640, Japan
  7. Laboratory of Neuropsychopharmacology, School of Natural Science and Technology, and
  8. Institute of Nature and Environmental Technology, Kanazawa University, Kanazawa 920-1192, Japan
  9. Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
  10. Department of Biochemistry, and,
  11. Department of Advanced Biological Sciences for Regeneration, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
  12. Central Clinical Laboratory, and,
  13. Department of Psychiatry, Kanazawa University Hospital, Kanazawa 920-8641, Japan
  14. Department of Biochemistry, Toyama University School of Medicine, Toyama 930-0194, Japan
  15. Nanao National Hospital, Nanao 920-8531, Japan
  16. Department of Biochemistry and Medical Chemistry, Krasnoyarsk State Medical Academy, Krasnoyarsk 660022, Russia
  17. Department of Physiology, Tokyo Medical University, Tokyo 160-8402, Japan
  18. These authors contributed equally to this work.

Correspondence to: Hirokazu Hirai1,5,6,18Haruhiro Higashida1,2,4 Correspondence and requests for materials should be addressed to H.H. (Email: haruhiro@med.kanazawa-u.ac.jp).

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CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.