Social Behaviour and Oxytocin Secretion in the Brain ... -

Social Behaviour and Oxytocin Secretion in the Brain ... -

RECENT ADVANCES in CLINICAL MEDICINESocial Behaviour and Oxytocin Secretion in the BrainRegulated by CD38 in Human and MiceHARUHIRO HIGASHIDA, OLGA LOPATINA, ALLA B. SALMINA, YU A.PICHUGINA, ANDREI A. SOUMAROKOV and TOSHIO MUNESUEKanazawa University Research Center for Child Mental Development, 13-1 Takaramachi,Kanazawa 920-8640, Japan and Departments of Psychiatry, Biochemistry, Medical,Pharmaceutical and Toxicological Chemistry, Krasnoyarsk Medical University,Krasnoyarsk 660022, - Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition,trust, love and bonding. Previously, we showed that Cd38, a proliferation marker in leukaemiacells, plays an important role in the hypothalamus in the process of OXT release in adult mice.Disruption of Cd38 (Cd38-/-) elicited impairment of maternal behaviour and male socialrecognition in adult mice (Nature, 446, 41, 2007), similar to the behaviour observed in Oxt andOXT receptor (Oxtr) gene knockout (Oxt-/- and Oxtr-/-, respectively) mice. Impairment was alsoprominent in Cd38-/- newborn mice. However, these behaviours were much milder than thoseobserved in Oxt-/- and Oxtr-/- mice. These phenotypes seemed to be caused by the high plasmaOXT levels during development from neonates to 3-week-old juvenile mice. These resultssuggest that secretion of OXT into the brain in a Cd38-dependent manner plays an important rolein the development of social behaviour. Based on these results in animal experiments, OXTtreatment for autistic subjects as a restore method has been proposed, and its use hasbegun in several hospitals.Key-words: - Oxytocin, Social recognition, Maternal behaviour, CD38, Autism1 IntroductionOxytocin (OXT), a nonapeptide involvedin reproduction, is synthesised in theparaventricular nucleus and supraopticnucleus of the hypothalamus, and travelsdown neuronal axons to the posteriorpituitary. It is secreted into the generalcirculation from the nerve endings of theneurohypophysis and into the brain fromdendrites. It is well known that OXT islinked to complex social behaviour [1-3].In humans, intranasal OXT may promoteISSN: 1790-5125 304 ISBN: 978-960-474-165-6

RECENT ADVANCES in CLINICAL MEDICINEtrust, gaze or face recognition andinfusion of OXT can increase generosity[2-4]. In rodents, OXT is highly involvedin social interaction, social recognition,pair bonding and maternal behaviour[1-3,5-8]. In addition, animal studies haveshown that increased levels of OXT in theearly postnatal period may affectbehaviour and last into adulthood, and thatsubcutaneous administration of low dosesof OXT facilitates social recognition [5].Two types of mice with OXT (Oxt) orOXT receptor (Oxtr) gene knockout(Oxt-/- or Oxtr-/-) show profound socialamnesia [5-8]. Social amnesia can be fullyrescued by injection of OXT into themedial amygdale in Oxt-/- mice.Impairment of social behaviour is clearlyobserved even in pups. Theseobservations suggest that OXT plays animportant role in social behaviour byOXTR stimulation during braindevelopment throughout the juvenile toadult stages [9].Recently, we reported that adult micewith a null mutation in Cd38, a “niceness”protein with ADP-ribosyl cyclase activity,showed deficiency in social behaviour dueto the abnormality of central andperipheral OXT secretion [9-11]. We alsoshowed that decreased formation of cyclicADP-ribose (cADPR) results indysfunction of Ca2+-induced Ca2+-releasefor OXT secretion in hypothalamic OXTneurons (Fig. 1). Here, we report therelationship between social behaviour andOXT levels in Cd38 knockout mice, andcompared the results among threedifferent genotypes: Oxt-/-, Oxtr-/- andCd38-/-. And we discuss on the usage ofOXT on treatment for autism patients.Fig. 1. A scheme showing thatCD38-dependent cADPR- and NAADPsensitiveintracellular Ca 2+ mobilizationfrom ryanodine receptors in microsomeshas a key role in oxytocin (OT) release.This system of OXT is important in socialbehaviour.2 Critical time window of plasmaOXT levels for adult from juvenilestagesThe decrease in OXT concentration afterweaning during development wasobserved only in Cd38-/- mice, suggestingan important critical period to distinguishdifferent plasma OXT switching from theISSN: 1790-5125 305 ISBN: 978-960-474-165-6

RECENT ADVANCES in CLINICAL MEDICINEjuvenile stage to the adult stage [11]. Asbreast milk is the only food source inlactating pups, we speculated that OXT isinevitably taken in from the breast milk.To confirm this, we performedquantitative analysis to determine whetherOXT is present in the mammary glands oflactating dams and milk in pups. Milkcurd was found in the stomachs of theoffspring born to Cd38-/- females,Fig. 2. Plasma OXT levels in twogenotyoes during development.which was quite different from that inthose of Oxt-/- and Oxtr-/- females. OXTwas abundant in the mammary glandtissue and breast milk in lactating dams ofboth genotypes, with no significantdifference between Cd38+/+and Cd38-/-animals. . In the three stages of growth anddevelopment, the plasma OXT seems tobe controlled from different sources:Foetal stage, Infant nt stage (breastfeedingstage) and Adult stage (weaning stage). Inwild-type mice, during all developmentalstages, OXT levels are kept high (Fig. 2).In contrast, in Cd38 knockout mice OXTlevels decreased significantly afterweaning [10,11].3 Implications for developmentaldisordersA series of recent studies suggested thatOXT is related to autism [13,14]. It hasbeen reported that plasma OXT levels inautistic children are lower than those inage-matched normal controls, althoughthe precise deviation is very small [15].Infusion of OXT reduces repetitivebehaviours in adults with autistic andAsperger’s disorders [16].. However, thesestudies have largely focused on autism inolder children and adults. There have beenonly a few studies in infants duringbreastfeeding and theperiod.early postnatalFig. 3. A scheme showing that nasal OXTinfusion or local CD38 expression in thehypothalamus can rescue socialimpairment in autistic subjects.ISSN: 1790-5125 306 ISBN: 978-960-474-165-6

RECENT ADVANCES in CLINICAL MEDICINEAlthough the exact mechanism is unclear[18], based on our data, we proposed thatlack of adequate exogenous OXT duringbreastfeeding would affect the normaldevelopment of the brain in geneticallysusceptible infants, thereby increasing therisk of autism (Fig. 3). OXT treatment as arefill method has been proposed, and itsuse has begun in several hospitals,including Kanazawa and KrasnoyarskUniversity Hospitals [19]. In some cases,we observed improvement in socialbehaviour, as might be suggested fromexperimental data and as it has beenreported previously [13,17].4 ConclusionWe concluded that different sources ofOXT seem to impact brain development atdifferent stages of growth, and thusmaintenance of high OXT level is securedfor development and social behaviour.OXT treatment with a nasal spray hasbeen proposed, and its use has begun inseveral hospitals.Reference1 Neumann ID. Brain oxytocin: a keyregulator of emotional and socialbehaviours in both females and males. JNeuroendocrinol 2008; 20: 858-865.2 Donaldson ZR, Young LJ. Oxytocin,vasopressin, and the neurogenetics ofsociality. Science 2008; 322: 900-904.3 Lee HJ, Macbeth AH, Pagani JH,Young WS 3rd. Oxytocin: the greatfacilitator of life. Prog Neurobiol 2009;88: 127-151.4 Kosfeld M, Heinrichs M, Zak PJ,Fischbacher U, Fehr E. OXT increasestrust in humans. Nature 2005; 435:673-676.5 Nishimori K, Young LJ, Guo Q, WangZ, Insel TR, Matzuk MM. Oxytocin isrequired for nursing but is not essentialfor parturition or reproductive behavior.Proc Natl Acad Sci USA 1996; 93:11699-11704.6 Ferguson JN, Aldag JM, Insel TR,Young LJ. OXT in the medial amygdalais essential for social recognition in themouse. J Neurosci 2001; 21:8278-8285.7 Pedersen CA, Vadlamudi SV, BocciaML, Amico JA. Maternal behaviordeficits in nulliparous OXT knockoutmice. Genes Brain Behav 2006; 3:274-281.8 Takayanagi Y, Yoshida M, Bielsky IF,Ross HE, Kawamata M, Onaka T,Yanagisawa T, Kimura T, Matzuk MM,Young LJ, Nishimori K. Pervasivesocial deficits, but normal parturition, inOXT receptor-deficient mice. Proc Natl.ISSN: 1790-5125 307 ISBN: 978-960-474-165-6

RECENT ADVANCES in CLINICAL MEDICINEAcad Sci USA 2005; 102: 16096-16101.9 Higashida H, Salmina AB,Olovyannikova RY, Hashii M,Yokoyama S, Koizumi K, Jin D, LiuHX, Lopatina O, Amina S, Islam MS,Huang JJ, Noda M. Cyclic ADP-riboseas a universal calcium signal moleculein the nervous system. Neurochem Int2007; 51: 192-199.10 Jin D, Liu HX, Hirai H, Torashima T,Nagai T, Lopatina O, Shnayder NA,Yamada K, Noda M, Seike T, Fujita K,Takasawa S, Yokoyama S, Koizumi K,Shiraishi Y, Tanaka S, Hashii M,Yoshihara T, Higashida K, Islam MS,Yamada N, Hayashi K, Noguchi N,Kato I, Okamoto H, Matsushima A,Salmina A, Munesue T, Shimizu N,Mochida S, Asano M, Higashida H.CD38 is critical for social behaviour byregulating OXT secretion. Nature 2007;446: 41-45.11 Liu HX, Lopatina O, Higashida C,Tsuji T, Kato I, Takasawa S, OkamotoH, Yokoyama S, Higashida H.Locomotor activity, ultrasonicvocalization and oxytocin levels ininfant CD38 knockout mice. NeurosciLett 2008; 448: 67-70.12 Lopatina O, Liu HX, Amina S, HashiiM, Higashida H. Oxytocin-inducedelevation of ADP-ribosyl cyclaseactivity, cyclic ADP-ribose or Ca(2+)concentrations is involved inautoregulation of oxytocin secretion inthe hypothalamus and posteriorpituitary in male mice.Neuropharmacology 2010; 58: 50-55.13 Heinrichs M, von Dawans B, Domes G.Oxytocin, vasopressin, and humansocial behavior. Front Neuroendocrinol2009; 30: 548-557.14 Yamasue H, Kuwabara H, KawakuboY, Kasai K. Oxytocin, sexuallydimorphic features of the social brain,and autism. Psychiatry Clin Neurosci2009; 63: 129-140.15 Modahl C, Green L, Fein D, Morris M,Waterhouse L, Feinstein C, Levin H.Plasma oxytocin levels in autisticchildren. Biol Psychiat 1998; 43:270-277.16 Hollander E, Novotny S, Hanratty M,Yaffe R, deCaria C, Aronowitz B.Oxytocin infusion reduces repetitivebehaviors in adults with autistic andAsperger’sdisorders.Neuropsychopharmacol 2003; 28:193-198.17 Macdonald K, Macdonald TM. Thepeptide that binds: a systematic reviewof oxytocin and its prosocial effects inhumans. Harv Rev Psychiatry 2010; 18:1-21.18 Ebstein RP, Israel S, Lerer E,Uzefovsky F, Shalev I, Gritsenko I,ISSN: 1790-5125 308 ISBN: 978-960-474-165-6

RECENT ADVANCES in CLINICAL MEDICINERiebold M, Salomon S, Yirmiya N.Arginine vasopressin and oxytocinmodulate human social behavior. AnnNY Acad Sci 2009; 1167: 87-102.19 Munesue T, Yokoyama S, NakamuraK, Anitha A, Yamada K, Hayashi K,Asaka T, Hong-Xiang Liu, Jin D,Koizumi K, Islam MS, Huang JJ, MaWJ, Kim UH, Kim SJ, Park KW, KimDS, Kikuchi M, Ono Y, Nakatani H,Suda S, Miyachi T, Hirai H, Salmina A,Pichugina YA, Soumarokov A, Takei N,Mori N, Tsujii M, Sugiyama T, Yagi K,Yamagishi M, Sasaki T, Yamasue H,Kato N, Hashimoto R, Taniike M,Hayashi Y, Hamada J, Suzuki S, Ooi A,Noda M, Kamiyama Y, Kido M,Shimizu N, Yoshikawa T, MatsushimaLopatina O, Hashii M, Amina S,Malavasi F, Huang EJ, Zhang JS,Shimizu N, Yoshikawa T, MatsushimaA, Minabe Y, Higashida H. Two geneticvariants of CD38 in subjects withautism spectrum disorder and controls.Neurosci Res In prpeparation.ISSN: 1790-5125 309 ISBN: 978-960-474-165-6

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