Olga L Lopatina

Publications

• 3.70

  Impact points

  Reproductive experience affects parental retrieval behaviour associated with increased plasma oxytocin levels in wild-type and CD38-knockout mice.

  O Lopatina, A Inzhutova, Y A Pichugina, H Okamoto, A B Salmina, H Higashida

  Journal of neuroendocrinology. 04/2011; 23(11):1125-33.

  The transition to motherhood results in a number of hormonal, neurological and behavioural changes necessary to ensure offspring growth. Once motherhood is established, further neurological and behavioural changes may result in long-term memory in mothering. Recent research has shown that postpartum... [more] The transition to motherhood results in a number of hormonal, neurological and behavioural changes necessary to ensure offspring growth. Once motherhood is established, further neurological and behavioural changes may result in long-term memory in mothering. Recent research has shown that postpartum motherhood enhances both nurturing behaviour and oxytocin activities. The transmembrane glycoprotein, CD38, is expressed on many neuronal cells and has been shown to play a role in social behaviours through stimulating the release of oxytocin in the hypothalamus. The present study was performed to investigate the effects of reproductive experience (primi- and multiparity, dams and sires) on the degree of parental behaviour, such as retrieval. Comparisons were performed between wild-type (Cd38 (+/+) ) and Cd38 knockout (Cd38 (-/-) ) mice of the ICR strain. Multiparous Cd38 (-/-) dams retrieved pups much faster than primiparous mice, whereas there were no significant differences between primi- and multiparous Cd38 (+/+) dams. Plasma oxytocin levels were significantly increased in multiparous dams of both genotypes. In addition, oxytocin levels in the hypothalamus and pituitary were lower in Cd38 (-/-) than in wild-type mice. ADP-ribosyl cyclase activity in the hypothalamus, but not in the pituitary, was slightly increased in Cd38 (+/+) dams. In an identical test, 40% of first-time Cd38 (+/+) sires showed retrieval. The time required to retrieval was shorter in second-time Cd38 (+/+) sires. Both first- and second-time Cd38 (-/-) sires showed only 10% retrieval behaviour. These results indicate that parental behaviour is improved by reproductive experience, especially in Cd38 (-/-) dams, and suggest that these effects may be a result of increased oxytocin levels.
• 1.81

  Impact points

  CD38 gene knockout juvenile mice: a model of oxytocin signal defects in autism.

  Haruhiro Higashida, Shigeru Yokoyama, Toshio Munesue, Mitsuru Kikuchi, Yoshio Minabe, Olga Lopatina

  Biological & pharmaceutical bulletin. 01/2011; 34(9):1369-72.

  Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD38, a leukaemia cell marker, plays an important role in the hypothalamus in the process of OXT release in adult mice. Disruption of Cd38 (Cd38(-/-)) produced impairment of maternal ... [more] Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD38, a leukaemia cell marker, plays an important role in the hypothalamus in the process of OXT release in adult mice. Disruption of Cd38 (Cd38(-/-)) produced impairment of maternal behavior and male social recognition in mice, similar to the behavior observed in Oxt and OXT receptor (Oxtr) gene knockout (Oxt(-/-) and Oxtr(-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalization (USV) calls was lower in Cd38(-/-) than Cd38(+/+) pups. These phenotypes seemed to be caused by the high plasma OXT levels during development from neonates to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of differentiating plasma OXT. Contribution by breastfeeding was an important exogenous source for regulating plasma OXT before weaning by the presence of OXT in milk and the dam's mammary glands. The dissimilarity of Cd38(-/-) infant behaviour to Oxt(-/-) or Oxtr(-/-) mice can be explained partly by this exogenous source of OXT. These results suggest that secretion of OXT into the brain in a CD38-dependent manner may play an important role in the development of social behavior, and mice with OXT signalling deficiency, including Cd38(-/-), Oxt(-/-) and Oxtr(-/-) mice are good animal models for developmental disorders, such as autism.
• 2.14

  Impact points

  Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.

  Toshio Munesue, Shigeru Yokoyama, Kazuhiko Nakamura, Ayyappan Anitha, Kazuo Yamada, Kenshi Hayashi, Tomoya Asaka, Hong-Xiang Liu, Duo Jin, Keita Koizumi, [......], Minako Hashii, Sarwat Amina, Fabio Malavasi, Eric J Huang, Jiasheng Zhang, Nobuaki Shimizu, Takeo Yoshikawa, Akihiro Matsushima, Yoshio Minabe, Haruhiro Higashida

  Neuroscience research. 06/2010; 67(2):181-91.

  The 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 t... [more] The 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.
• 3.70

  Impact points

  CD38/cyclic ADP-ribose system: a new player for oxytocin secretion and regulation of social behaviour.

  A B Salmina, O Lopatina, M V Ekimova, S V Mikhutkina, H Higashida

  Journal of neuroendocrinology. 02/2010; 22(5):380-92.

  Oxytocin is important for regulating a number of physiological processes. Disruption of the secretion, metabolism or action of oxytocin results in an impairment of reproductive function, social and sexual behaviours, and stress responses. This review discusses current views on the regulation and aut... [more] Oxytocin is important for regulating a number of physiological processes. Disruption of the secretion, metabolism or action of oxytocin results in an impairment of reproductive function, social and sexual behaviours, and stress responses. This review discusses current views on the regulation and autoregulation of oxytocin release in the hypothalamic-neurohypophysial system, with special focus on the activity of the CD38/cADP-ribose system as a new component in this regulation. Data from our laboratories indicate that an impairment of this system results in alterations of oxytocin secretion and abnormal social behaviour, thus suggesting new clues that help in our understanding of the pathogenesis of neurodevelopmental disorders.
• 3.70

  Impact points

  Oxytocin signal and social behaviour: comparison among adult and infant oxytocin, oxytocin receptor and CD38 gene knockout mice.

  H Higashida, O Lopatina, T Yoshihara, Y A Pichugina, A A Soumarokov, T Munesue, Y Minabe, M Kikuchi, Y Ono, N Korshunova, A B Salmina

  Journal of neuroendocrinology. 02/2010; 22(5):373-9.

  Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 (Cd38 (-/-... [more] Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 (Cd38 (-/-)) elicited impairment of maternal behaviour and male social recognition in adult mice, similar to the behaviour observed in Oxt and oxytocin receptor (Oxtr) gene knockout (Oxt (-/-) and Oxtr (-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalisation calls was lower in Cd38 (-/-) than Cd38( +/+) pups. However, these behavioural changes were much milder than those observed in Oxt (-/-) and Oxtr (-/-) mice, indicating less impairment of social behaviour in Cd38 (-/-) pups. These phenotypes appeared to be caused by the high plasma oxytocin levels during development from the neonatal period to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of plasma oxytocin differentiation. Breastfeeding was an important exogenous source of plasma oxytocin regulation before weaning as a result of the presence of oxytocin in milk and the dam's mammary glands. The dissimilarity between Cd38 (-/-) infant behaviour and those of Oxt (-/-) or Oxtr (-/-) mice can be explained partly by this exogenous source of oxytocin. These results suggest that secretion of oxytocin into the brain in a CD38-dependent manner may play an important role in the development of social behaviour.
• 3.70

  Impact points

  Intracellular calcium elevation induced by extracellular application of cyclic-ADP-ribose or oxytocin is temperature-sensitive in rodent NG108-15 neuronal cells with or without exogenous expression of human oxytocin receptors.

  S Amina, M Hashii, W-J Ma, S Yokoyama, O Lopatina, H-X Liu, M S Islam, H Higashida

  Journal of neuroendocrinology. 02/2010; 22(5):460-6.

  ADP-ribosyl cyclase and/or CD38 are activated after oxytocin receptor stimulation in the hypothalamus and pituitary in adult mice, leading to facilitation of oxytocin secretion. Although cyclic adenosine 5'-diphosphoribose (cADPR) primarily acts as an intracellular second messenger, it has been ... [more] ADP-ribosyl cyclase and/or CD38 are activated after oxytocin receptor stimulation in the hypothalamus and pituitary in adult mice, leading to facilitation of oxytocin secretion. Although cyclic adenosine 5'-diphosphoribose (cADPR) primarily acts as an intracellular second messenger, it has been suggested that extracellular cADPR stimulates intracellular ryanodine receptors after internalisation via the nucleotide-transporting capacity of CD38 in fibroblasts and astrocytes. However, little is known about whether extracellular cADPR activates neurones. To address this question, we used a model neuronal cell line, NG108-15 mouse neuroblastoma x rat glioma hybrid cells possessing CD38 but not oxytocin receptors, and measured cytosolic free calcium concentrations ([Ca(2+)](i)). Extracellular application of cADPR to NG108-15 cells elevated [Ca(2+)](i) at 35 degrees C. The elevation was significantly enhanced when measured at 40 degrees C. The cADPR and heat-induced [Ca(2+)](i) increase were blocked under extracellular Ca(2+)-free conditions and by 2-aminoethoxydiphenyl borate, an antagonist of melastatin-related transient receptor potential channel 2 (TRPM2) cation channels. Reverse transcriptation-polymerase chain reaction analyses indicated that TRPM2 channels were expressed in NG108-15 cells. Application of oxytocin elevated [Ca(2+)](i) in NG108-15 cells transformed to transiently express cloned human oxytocin receptors. The oxytocin-induced [Ca(2+)](i) response was also enhanced by heat. These results indicate that the extracellular application of cADPR, together with heat, activates cation influx downstream of oxytocin receptor signalling in NG108-15 neuronal cells, and suggest the possible involvement of TRPM2 channels in oxytocin release in the mammalian brain.

• Oxytocin-induced elevation of ADP-ribosyl cyclase activity, cyclic ADP-ribose or Ca(2+) concentrations is involved in autoregulation of oxytocin secretion in the hypothalamus and posterior pituitary in male mice.

  Olga Lopatina, Hong-Xiang Liu, Sarwat Amina, Minako Hashii, Haruhiro Higashida

  Neuropharmacology. 07/2009;

  Locally released oxytocin (OT) activates OT receptors (2.1:OXY:1:OT:) in neighboring neurons in the hypothalamus and their terminals in the posterior pituitary, resulting in further OT release, best known in autoregulation occurring during labor or milk ejection in reproductive females. OT also play... [more] Locally released oxytocin (OT) activates OT receptors (2.1:OXY:1:OT:) in neighboring neurons in the hypothalamus and their terminals in the posterior pituitary, resulting in further OT release, best known in autoregulation occurring during labor or milk ejection in reproductive females. OT also plays a critical role in social behavior of non-reproductive females and even in males in mammals from rodents to humans. Social behavior is disrupted when elevation of free intracellular Ca(2+) concentration ([Ca(2+)](i)) and OT secretion are reduced in male and female CD38 knockout mice. Therefore, it is interesting to investigate whether ADP-ribosyl cyclase-dependent signaling is involved in OT-induced OT release for social recognition in males, independent from female reproduction, and to determine its molecular mechanism. Here, we report that ADP-ribosyl cyclase activity was increased by OT in crude membrane preparations of the hypothalamus and posterior pituitary in male mice, and that OT elicited an increase in [Ca(2+)](i) in the isolated terminals over a period of 5min. The increases in cyclase and [Ca(2+)](i) were partially inhibited by nonspecific protein kinase inhibitors and a protein kinase C specific inhibitor, calphostin C. Subsequently, OT-induced OT release was also inhibited by calphostin C to levels inhibited by vasotocin, an OT receptor antagonist, and 8-bromo-cADP-ribose. These results demonstrate that OT receptors are functionally coupled to membrane-bound ADP-ribosyl cyclase and/or CD38 and suggest that cADPR-mediated intracellular calcium signaling is involved in autoregulation of OT release, which is sensitive to protein kinase C, in the hypothalamus and neurohypophysis in male mice.
• 1.93

  Impact points

  Locomotor activity, ultrasonic vocalization and oxytocin levels in infant CD38 knockout mice.

  Hong-Xiang Liu, Olga Lopatina, Chiharu Higashida, Takahiro Tsuji, Ichiro Kato, Shin Takasawa, Hiroshi Okamoto, Shigeru Yokoyama, Haruhiro Higashida

  Neuroscience letters. 10/2008;

  Oxytocin (OT), a neurohormone involved in reproduction, plays a critical role in social behavior in a wide range of mammalian species from rodents to humans. The role of CD38 in regulating OT secretion for social behavior has been demonstrated in adult mice, but has not been examined in pups or duri... [more] Oxytocin (OT), a neurohormone involved in reproduction, plays a critical role in social behavior in a wide range of mammalian species from rodents to humans. The role of CD38 in regulating OT secretion for social behavior has been demonstrated in adult mice, but has not been examined in pups or during development. Separation from the dam induces stress in 7-day-old mouse pups. During such isolation, locomotor activity was higher in CD38 knockout (CD38(-/-)) pups than in wild-type (CD38(+/+)) or heterozygous (CD38(+/-)) controls. The number of ultrasonic vocalizations was lower in CD38(-/-) pups than in CD38(+/+) pups. However, the difference between the two genotypes was less severe than in OT knockout or OT receptor knockout mice. To explain this, we measured plasma OT levels. The level was not lower in CD38(-/-) pups during the period 1-3 weeks after birth, but was significantly reduced after weaning (</=3 weeks). ADP-ribosyl cyclase activities in the hypothalamus and pituitary were markedly lower from 1 week after birth in CD38(-/-) mice and were consistently lower thereafter to the adult stage (2 months old). These results showed that the reduced severity of behavioral abnormalities in CD38(-/-) pups was due to partial compensation by the high level of plasma OT.
• 34.48

  Impact points

  CD38 is critical for social behaviour by regulating oxytocin secretion.

  Duo Jin, Hong-Xiang Liu, Hirokazu Hirai, Takashi Torashima, Taku Nagai, Olga Lopatina, Natalia A Shnayder, Kiyofumi Yamada, Mami Noda, Toshihiro Seike, [......], Naoya Noguchi, Ichiro Kato, Hiroshi Okamoto, Akihiro Matsushima, Alla Salmina, Toshio Munesue, Nobuaki Shimizu, Sumiko Mochida, Masahide Asano, Haruhiro Higashida

  Nature. 04/2007; 446(7131):41-5.

  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 ... [more] 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.
• 3.54

  Impact points

  Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system.

  Haruhiro Higashida, Alla B. Salmina, Raissa Ya Olovyannikova, Minako Hashii, Shigeru Yokoyama, Keita Koizumi, Duo Jin, Hong-Xiang Liu, Olga Lopatina, Sarwat Amina, Mohammad Saharul Islam, Jian-Jun Huang, Mami Noda

  Neurochemistry international. 51(2-4):192-9.

  beta-NAD(+) is as abundant as ATP in neuronal cells. beta-NAD(+) functions not only as a coenzyme but also as a substrate. beta-NAD(+)-utilizing enzymes are involved in signal transduction. We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a universal Ca(2+) mobilizer... [more] beta-NAD(+) is as abundant as ATP in neuronal cells. beta-NAD(+) functions not only as a coenzyme but also as a substrate. beta-NAD(+)-utilizing enzymes are involved in signal transduction. We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a universal Ca(2+) mobilizer from intracellular stores, from beta-NAD(+). cADPR acts through activation/modulation of ryanodine receptor Ca(2+) releasing Ca(2+) channels. cADPR synthesis in neuronal cells is stimulated or modulated via different pathways and various factors. Subtype-specific coupling of various neurotransmitter receptors with ADP-ribosyl cyclase confirms the involvement of the enzyme in signal transduction in neurons and glial cells. Moreover, cADPR/CD38 is critical in oxytocin release from the hypothalamic cell dendrites and nerve terminals in the posterior pituitary. Therefore, it is possible that pharmacological manipulation of intracellular cADPR levels through ADP-ribosyl cyclase activity or synthetic cADPR analogues may provide new therapeutic opportunities for treatment of neurodevelopmental disorders.

• Oxytocin signal and social behaviour: comparison among adult and infant oxytocin, oxytocin receptor and CD38 gene knockout mice.

  Haruhiro Higashida, Olga A. Lopatina, T. Yoshihara, Yu A. Pichugina, Andrei A. Soumarokov, Toshio Munesue, Yoshio Minabe, Mitsuru Kikuchi, Yasuki Ono, N. Korshunova, Alla B. Salmina

  Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 (Cd38 (-/-... [more] Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 (Cd38 (-/-)) elicited impairment of maternal behaviour and male social recognition in adult mice, similar to the behaviour observed in Oxt and oxytocin receptor (Oxtr) gene knockout (Oxt (-/-) and Oxtr (-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalisation calls was lower in Cd38 (-/-) than Cd38( +/+) pups. However, these behavioural changes were much milder than those observed in Oxt (-/-) and Oxtr (-/-) mice, indicating less impairment of social behaviour in Cd38 (-/-) pups. These phenotypes appeared to be caused by the high plasma oxytocin levels during development from the neonatal period to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of plasma oxytocin differentiation. Breastfeeding was an important exogenous source of plasma oxytocin regulation before weaning as a result of the presence of oxytocin in milk and the dam's mammary glands. The dissimilarity between Cd38 (-/-) infant behaviour and those of Oxt (-/-) or Oxtr (-/-) mice can be explained partly by this exogenous source of oxytocin. These results suggest that secretion of oxytocin into the brain in a CD38-dependent manner may play an important role in the development of social behaviour.

• [The role of P2X7 receptors in modulation of the functional activity of peritoneal macrophages in mice with peritonitis].

  N A Malinovskaia, A B Salmina, A A Karacheva, V V Salmin, Iu A Uspenskaia, O L Lopatina, A G Sokolovich, A V Stepanenko, O V Per'ianova, L D Zykova

  Eksperimental'naia i klinicheskaia farmakologiia. 71(3):49-53.

  The role of P2X7 receptors in modulation of the functional activity of macrophages in mice with model peritonitis has been studied. It is established that the functional activity of murine macrophages under such conditions is increased, which is accompanied by the growth of P2X7(+) macrophages and a... [more] The role of P2X7 receptors in modulation of the functional activity of macrophages in mice with model peritonitis has been studied. It is established that the functional activity of murine macrophages under such conditions is increased, which is accompanied by the growth of P2X7(+) macrophages and a bidirectional change of the their functional activity under the action of P2X7 modulators. The role of P2X7-associated mechanisms in regulation of the macrophage activity during inflammation is discussed.