Haruhiro Higashida
Research interests
-
InterestsHypothalamo-Hypophyseal System, Oxytocin, Social Behavior, Autism Spectrum Disorders
Publications
-
1.93Impact points
Spatiotemporal frequency characteristics of cerebral oscillations during the perception of fundamental frequency contour changes in one-syllable intonation.
Neuroscience letters. 03/2012;
Accurate perception of fundamental frequency (F0) contour changes in the human voice is important for understanding a speaker's intonation, and consequently also his/her attitude. In this study, we investigated the neural processes involved in the perception of F0 contour changes in the Japanese... [more] Accurate perception of fundamental frequency (F0) contour changes in the human voice is important for understanding a speaker's intonation, and consequently also his/her attitude. In this study, we investigated the neural processes involved in the perception of F0 contour changes in the Japanese one-syllable interjection "ne" in 21 native-Japanese listeners. A passive oddball paradigm was applied in which "ne" with a high falling F0 contour, used when urging a reaction from the listener, was randomly presented as a rare deviant among a frequent "ne" syllable with a flat F0 contour (i.e., meaningless intonation). We applied an adaptive spatial filtering method to the neuromagnetic time course recorded by whole-head magnetoencephalography (MEG) and estimated the spatiotemporal frequency dynamics of event-related cerebral oscillatory changes in the oddball paradigm. Our results demonstrated a significant elevation of beta band event-related desynchronization (ERD) in the right temporal and frontal areas, in time windows from 100 to 300 and from 300 to 500ms after the onset of deviant stimuli (high falling F0 contour). This is the first study to reveal detailed spatiotemporal frequency characteristics of cerebral oscillations during the perception of intonational (not lexical) F0 contour changes in the human voice. The results further confirmed that the right hemisphere is associated with perception of intonational F0 contour information in the human voice, especially in early time windows.
-
3.54Impact points
Ect2, an ortholog of Drosophila Pebble, regulates formation of growth cones in primary cortical neurons.
Neurochemistry international. 02/2012;
In collaboration with Marshall Nirenberg, we performed in vivo RNA interference (RNAi) genome-wide screening in Drosophila embryos. Pebble has been shown to be involved in Drosophila neuronal development. We have also reported that depletion of Ect2, a mammalian ortholog of Pebble, induces different... [more] In collaboration with Marshall Nirenberg, we performed in vivo RNA interference (RNAi) genome-wide screening in Drosophila embryos. Pebble has been shown to be involved in Drosophila neuronal development. We have also reported that depletion of Ect2, a mammalian ortholog of Pebble, induces differentiation in NG108-15 neuronal cells. However, the precise role of Ect2 in neuronal development has yet to be studied. Here, we confirmed in PC12 pheochromocytoma cells that inhibition of Ect2 expression by RNAi stimulated neurite outgrowth, and in the mouse embryonic cortex that Ect2 was accumulated throughout the ventricular and subventricular zones with neuronal progenitor cells. Next, the effects of Ect2 depletion were studied in primary cultures of mouse embryonic cortical neurons: Loss of Ect2 did not affect the differentiation stages of neuritogenesis, the number of neurites, or axon length, while the numbers of growth cones and growth cone-like structures were increased. Taken together, our results suggest that Ect2 contributes to neuronal morphological differentiation through regulation of growth cone dynamics.
-
3.54Impact points
Social memory, amnesia, and autism: Brain oxytocin secretion is regulated by NAD(+) metabolites and single nucleotide polymorphisms of CD38.
Neurochemistry international. 02/2012;
Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knocko... [more] Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. The autism spectrum disorders (ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. However, the etiology of ASDs remains largely unknown. Therefore, the theoretical basis for pharmacological treatments has not been established. Hence, there is a rationale for investigating single nucleotide polymorphisms (SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 (C>A) was associated with high-functioning autism (HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C>T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W; R140W) in CD38. This mutation was found in four probands of ASD and in family members of three pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. The OXT levels were unchanged in healthy subjects with or without this mutation. One proband with the R140W allele receiving intranasal OXT for approximately 3years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods; three subjects showed improved symptoms, while two showed little or no effect. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials.
-
3.42Impact points
Language performance and auditory evoked fields in 2- to 5-year-old children.
The European journal of neuroscience. 02/2012; 35(4):644-50.
Language development progresses at a dramatic rate in preschool children. As rapid temporal processing of speech signals is important in daily colloquial environments, we performed magnetoencephalography (MEG) to investigate the linkage between speech-evoked responses during rapid-rate stimulus pres... [more] Language development progresses at a dramatic rate in preschool children. As rapid temporal processing of speech signals is important in daily colloquial environments, we performed magnetoencephalography (MEG) to investigate the linkage between speech-evoked responses during rapid-rate stimulus presentation (interstimulus interval < 1 s) and language performance in 2- to 5-year-old children (n = 59). Our results indicated that syllables with this short stimulus interval evoked detectable P50m, but not N100m, in most participants, indicating a marked influence of longer neuronal refractory period for stimulation. The results of equivalent dipole estimation showed that the intensity of the P50m component in the left hemisphere was positively correlated with language performance (conceptual inference ability). The observed positive correlations were suggested to reflect the maturation of synaptic organisation or axonal maturation and myelination underlying the acquisition of linguistic abilities. The present study is among the first to use MEG to study brain maturation pertaining to language abilities in preschool children.
-
3.54Impact points
Dopamine release via the vacuolar ATPase V0 sector c-subunit, confirmed in N18 neuroblastoma cells, results in behavioral recovery in hemiparkinsonian mice.
Neurochemistry international. 01/2012;
A 16-kDa proteolipid, mediatophore, in Torpedo electric organs mediates Ca(2+)-dependent acetylcholine release. Mediatophore is identical to the pore-forming stalk c-subunit of the V0 sector of vacuolar proton ATPase (ATP6V0C). The function of ATP6V0C in the mammalian central nervous system is not c... [more] A 16-kDa proteolipid, mediatophore, in Torpedo electric organs mediates Ca(2+)-dependent acetylcholine release. Mediatophore is identical to the pore-forming stalk c-subunit of the V0 sector of vacuolar proton ATPase (ATP6V0C). The function of ATP6V0C in the mammalian central nervous system is not clear. Here, we report transfection of adeno-associated viral vectors harboring rat ATP6V0C into the mouse substantia nigra, in which high potassium stimulation increased overflow of endogenous dopamine (DA) measured in the striatum by in vivo microdialysis. Next, in the striatum of 6-hydroxydopamine-lesioned mice, a model of Parkinson's disease (PD), human tyrosine hydroxylase, aromatic l-amino-acid decarboxylase and guanosine triphosphate cyclohydrolase 1, together with or without ATP6V0C, were expressed in the caudoputamen for rescue. Motor performance on the accelerating rotarod test and amphetamine-induced ipsilateral rotation were improved in the rescued mice coexpressing ATP6V0C. [(3)H]DA, taken up into cultured N18 neuronal tumor cells transformed to express ATP6V0C, was released by potassium stimulation. These results indicated that ATP6V0C mediates DA release from nerve terminals in the striatum of DA neurons of normal mice and from gene-transferred striatal cells of parkinsonian mice. The results suggested that ATP6V0C may be useful as a rescue molecule in addition to DA-synthetic enzymes in the gene therapy of PD.
-
Oxytocin attenuates feelings of hostility depending on emotional context and individuals' characteristics.
Scientific reports. 01/2012; 2:384.
In humans, oxytocin (OT) enhances prosocial behaviour. However, it is still unclear how the prosocial effects of OT are modulated by emotional features and/or individuals' characteristics. In a placebo-controlled design, we tested 20 healthy male volunteers to investigate these behavioural and n... [more] In humans, oxytocin (OT) enhances prosocial behaviour. However, it is still unclear how the prosocial effects of OT are modulated by emotional features and/or individuals' characteristics. In a placebo-controlled design, we tested 20 healthy male volunteers to investigate these behavioural and neurophysiological modulations using magnetoencephalography. As an index of the individuals' characteristics, we used the empathy quotient (EQ), the autism spectrum quotient (AQ), and the systemising quotient (SQ). Only during the perception of another person's angry face was a higher SQ a significant predictor of OT-induced prosocial change, both in the behavioural and neurophysiological indicators. In addition, a lower EQ was only a significant predictor of OT-induced prosocial changes in the neurophysiological indicators during the perception of angry faces. Both on the behavioural and the neurophysiological level, the effects of OT were specific for anger and correlated with a higher SQ.
-
3.77Impact points
CD38 and its role in oxytocin secretion and social behavior.
Hormones and behavior. 12/2011;
Here, we review the functional roles of cyclic ADP-ribose and CD38, a transmembrane protein with ADP-ribosyl cyclase activity, in mouse social behavior via the regulation of oxytocin (OXT) release, an essential component of social cognition. Herein we describe data detailing the molecular mechanism ... [more] Here, we review the functional roles of cyclic ADP-ribose and CD38, a transmembrane protein with ADP-ribosyl cyclase activity, in mouse social behavior via the regulation of oxytocin (OXT) release, an essential component of social cognition. Herein we describe data detailing the molecular mechanism of CD38-dependent OXT secretion in CD38 knockout mice. We also review studies that used OXT, OXT receptor (OXTR), or CD38 knockout mice. Additionally, we compare the behavioral impairments that occur in these knockout mice in relation to the OXT system and CD38. This review also examines autism spectrum disorder (ASD), which is characterized by social and communication impairments, in relation to defects in the OXT system. Two single nucleotide polymorphisms (SNPs) in the human CD38 gene are possible risk factors for ASD via inhibition of OXT function. Further analysis of CD38 in relation to the OXT system may provide a better understanding of the neuroendocrinological roles of OXT and CD38 in the hypothalamus and of the pathophysiology of ASD.
-
7.18Impact points
Lateralized theta wave connectivity and language performance in 2- to 5-year-old children.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 10/2011; 31(42):14984-8.
Recent neuroimaging studies support the view that a left-lateralized brain network is crucial for language development in children. However, no previous studies have demonstrated a clear link between lateralized brain functional network and language performance in preschool children. Magnetoencephal... [more] Recent neuroimaging studies support the view that a left-lateralized brain network is crucial for language development in children. However, no previous studies have demonstrated a clear link between lateralized brain functional network and language performance in preschool children. Magnetoencephalography (MEG) is a noninvasive brain imaging technique and is a practical neuroimaging method for use in young children. MEG produces a reference-free signal, and is therefore an ideal tool to compute coherence between two distant cortical rhythms. In the present study, using a custom child-sized MEG system, we investigated brain networks while 78 right-handed preschool human children (32-64 months; 96% were 3-4 years old) listened to stories with moving images. The results indicated that left dominance of parietotemporal coherence in theta band activity (6-8 Hz) was specifically correlated with higher performance of language-related tasks, whereas this laterality was not correlated with nonverbal cognitive performance, chronological age, or head circumference. Power analyses did not reveal any specific frequencies that contributed to higher language performance. Our results suggest that it is not the left dominance in theta oscillation per se, but the left-dominant phase-locked connectivity via theta oscillation that contributes to the development of language ability in young children.
-
Decreased expression of axon-guidance receptors in the anterior cingulate cortex in autism.
Molecular autism. 08/2011; 2(1):14.
ABSTRACT: Axon-guidance proteins play a crucial role in brain development. As the dysfunction of axon-guidance signaling is thought to underlie the microstructural abnormalities of the brain in people with autism, we examined the postmortem brains of people with autism to identify any changes in the... [more] ABSTRACT: Axon-guidance proteins play a crucial role in brain development. As the dysfunction of axon-guidance signaling is thought to underlie the microstructural abnormalities of the brain in people with autism, we examined the postmortem brains of people with autism to identify any changes in the expression of axon-guidance proteins. The mRNA and protein expression of axon-guidance proteins, including ephrin (EFN)A4, eEFNB3, plexin (PLXN)A4, roundabout 2 (ROBO)2 and ROBO3, were examined in the anterior cingulate cortex and primary motor cortex of autistic brains (n = 8 and n = 7, respectively) and control brains (n = 13 and n = 8, respectively) using real-time reverse-transcriptase PCR (RT-PCR) and western blotting. Real-time RT-PCR revealed that the relative expression levels of EFNB3, PLXNA4A and ROBO2 were significantly lower in the autistic group than in the control group. The protein levels of these three genes were further analyzed by western blotting, which showed that the immunoreactive values for PLXNA4 and ROBO2, but not for EFNB3, were significantly reduced in the ACC of the autistic brains compared with control brains. In this study, we found decreased expression of axon-guidance proteins such as PLXNA4 and ROBO2 in the brains of people with autism, and suggest that dysfunctional axon-guidance protein expression may play an important role in the pathophysiology of autism.
-
A Missense Mutation in CD38 Associated with Autism Spectrum Disorder in Three Pedigrees
08/2011;
ISBN: 978-953-307-493-1
-
2.11Impact points
Ect2, an ortholog of Drosophila's pebble, negatively regulates neurite outgrowth in neuroblastoma × glioma hybrid NG108-15 cells.
Cellular and molecular neurobiology. 02/2011; 31(5):663-8.
To identify genes required for brain development, we previously performed in vivo RNA interference (RNAi) screening in Drosophila embryos. We identified pebble as a gene that disrupts development of the Drosophila nervous system. Although pebble has been shown to be involved in neuronal development ... [more] To identify genes required for brain development, we previously performed in vivo RNA interference (RNAi) screening in Drosophila embryos. We identified pebble as a gene that disrupts development of the Drosophila nervous system. Although pebble has been shown to be involved in neuronal development of Drosophila in several screens, the involvement of Ect2, a mammalian ortholog of pebble, in mammalian neuronal development has not been addressed. To examine the role of Ect2 in neuronal differentiation, we performed Ect2 RNAi in the mouse neuroblastoma × rat glioma NG108-15 cell line. Depletion of Ect2 resulted in an increased proportion of binucleate cells and morphological differentiation of NG108-15 cells characterized by the outgrowth of neurites. These morphological changes were correlated with an increased level of acetylcholine esterase mRNA. In addition, expression of Ect2 was decreased in differentiated NG108-15 cells induced by dibutyryl cyclic AMP. These findings indicate that Ect2 negatively regulates the differentiation of NG108-15 cells and suggest that Ect2 may play a role in neuronal differentiation and brain development in vivo.
-
1.81Impact points
CD38 gene knockout juvenile mice: a model of oxytocin signal defects in autism.
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.
-
1.81Impact points
Neurovascular coupling in the human somatosensory cortex: a single trial study.
Neuroreport. 12/2010; 21(17):1106-10.
Oscillations in the higher frequency range are closely related to regional brain hemodynamic changes. Here we investigated this neurovascular coupling in humans in response to electrical stimulation of the right median nerve. In a single-trial study, we simultaneously recorded hemodynamic fluctuatio... [more] Oscillations in the higher frequency range are closely related to regional brain hemodynamic changes. Here we investigated this neurovascular coupling in humans in response to electrical stimulation of the right median nerve. In a single-trial study, we simultaneously recorded hemodynamic fluctuations in the somatosensory cortex by near infrared spectroscopy and brain neuronal oscillations by whole-head magnetoencephalography (MEG). The results from six volunteers showed that neural fluctuations at β or γ-band power were correlated with hemodynamic fluctuation during stimulus conditions. These correlations were prominent with a time delay of 5-7 s. This study provides new direct evidence that hemodynamic onset lags specific neural oscillations in the order of seconds in human awake conditions using noninvasive methods.
-
4.97Impact points
A KCR1 variant implicated in susceptibility to the long QT syndrome.
Journal of molecular and cellular cardiology. 10/2010; 50(1):50-7.
The acquired long QT syndrome (aLQTS) is frequently associated with extrinsic and intrinsic risk factors including therapeutic agents that inadvertently inhibit the KCNH2 K(+) channel that underlies the repolarizing I(Kr) current in the heart. Previous reports demonstrated that K(+) channel regulato... [more] The acquired long QT syndrome (aLQTS) is frequently associated with extrinsic and intrinsic risk factors including therapeutic agents that inadvertently inhibit the KCNH2 K(+) channel that underlies the repolarizing I(Kr) current in the heart. Previous reports demonstrated that K(+) channel regulator 1 (KCR1) diminishes KCNH2 drug sensitivity and may protect susceptible patients from developing aLQTS. Here, we describe a novel variant of KCR1 (E33D) isolated from a patient with ventricular fibrillation and significant QT prolongation. We recorded the KCNH2 current (I(KCNH2)) from CHO-K1 cells transfected with KCNH2 plus wild type (WT) or mutant KCR1 cDNA, using whole cell patch-clamp techniques and assessed the development of I(KCNH2) inhibition in response to well-characterized KCNH2 inhibitors. Unlike KCR1 WT, the E33D variant did not protect KCNH2 from the effects of class I antiarrhythmic drugs such as quinidine or class III antiarrhythmic drugs including dofetilide and sotalol. The remaining current of the KCNH2 WT+KCR1 E33D channel after 100 pulses in the presence of each drug was similar to that of KCNH2 alone. Simulated conditions of hypokalemia (1mM [K(+)](o)) produced no significant difference in the fraction of the current that was protected from dofetilide inhibition with KCR1 WT or E33D. The previously described α-glucosyltransferase activity of KCR1 was found to be compromised in KCR1 E33D in a yeast expression system. Our findings suggest that KCR1 genetic variations that diminish the ability of KCR1 to protect KCNH2 from inhibition by commonly used therapeutic agents constitute a risk factor for the aLQTS.
-
2.14Impact points
Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.
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.
-
4.56Impact points
Trafficking-competent KCNQ1 variably influences the function of HERG long QT alleles.
Heart rhythm : the official journal of the Heart Rhythm Society. 03/2010; 7(7):973-80.
Mutations in the KCNQ1 and human ether-a-go-go-related gene (HERG) genes cause the long QT syndromes, LQTS1 and LQTS2, due to reductions in the cardiac repolarizing I(Ks) and I(Kr) currents, respectively. It was previously reported that KCNQ1 coexpression modulates HERG function by enhancing membran... [more] Mutations in the KCNQ1 and human ether-a-go-go-related gene (HERG) genes cause the long QT syndromes, LQTS1 and LQTS2, due to reductions in the cardiac repolarizing I(Ks) and I(Kr) currents, respectively. It was previously reported that KCNQ1 coexpression modulates HERG function by enhancing membrane expression of HERG, and that the 2 proteins coimmunoprecipitate, and colocalize in myocytes. In vivo studies in genetically modified rabbits also support a HERG-KCNQ1 interaction. We sought to determine whether KCNQ1 influences the current characteristics of HERG genetic variants. This study used expression of HERG and KCNQ1 wild-type (WT) and mutant channels in heterologous systems, combined with whole-cell patch clamp analysis and biochemistry. Supporting the notion that KCNQ1 needs to be trafficking competent to influence HERG function, we found that although the tail current density of HERG expressed in Chinese Hamster Ovary (CHO) cells was approximately doubled by WT KCNQ1 coexpression, it was not altered in the presence of the trafficking-defective KCNQ1(T587M) variant. Activation and deactivation kinetics of HERG variants were not altered. The HERG(M124T) variant, previously shown to be mildly impaired functionally, was restored to WT levels by KCNQ1-WT but not KCNQ1(T587M) coexpression. The tail current densities of the severely trafficking-impaired HERG(G601S) and HERG(F805C) variants were only slightly improved by KCNQ1 coexpression. The trafficking competent but incompletely processed HERG(N598Q), and a mutation in the selectivity filter, HERG(G628S), were not improved by KCNQ1 coexpression. These findings suggest a functional codependence of HERG on KCNQ1 during channel biogenesis. Moreover, KCNQ1 variably modulates LQTS2 mutations with distinct underlying pathologies.
-
3.70Impact points
CD38/cyclic ADP-ribose system: a new player for oxytocin secretion and regulation of social behaviour.
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.
-
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.
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.
-
3.98Impact points
Long QT syndrome and associated gene mutation carriers in Japanese children: Results from ECG screening examination.
Clinical science (London, England : 1979). 04/2009;
Background: The long QT syndrome (LQTS) is caused by mutations in the cardiac ion channel genes. The prevalence of LQTS in the general population is not well known. Objective: We prospectively estimated the prevalence of LQTS and analyzed the associated mutation carriers in Japanese children. Method... [more] Background: The long QT syndrome (LQTS) is caused by mutations in the cardiac ion channel genes. The prevalence of LQTS in the general population is not well known. Objective: We prospectively estimated the prevalence of LQTS and analyzed the associated mutation carriers in Japanese children. Methods: ECGs were recorded from 7961 Japanese school children (4044 males, mean age 9.9 +/- 3.0 years). ECGs were again examined for the children who showed prolonged QTc intervals in the initial ECGs, and their QT intervals were measured manually. An LQTS score was determined by Schwartz's criteria, and ion channel genes were analyzed. In vitro characterization of identified mutants was performed by heterologous expression experiments. Results: Three subjects were assigned to a high probability of LQTS (3.5 </= LQTS score), and 8 to an intermediate probability (1.0 < LQTS score </= 3.0). Genetic analysis of these 3 subjects identified three HERG mutations (M124T, 547-553 del GGCGGCG, 2311-2332 del / ins TC). In contrast, no mutation was identified in the 15 subjects with a low probability. Electrophysiological studies showed that both the M124T and the 547-553 del HERG did not suppress the wild type HERG channel in a dominant negative manner. Conclusion: These results demonstrate that, in a random sample of healthy Japanese children, the prevalence of a high probability of LQTS is 0.038% (3/7961), and that LQTS mutation carriers can be identified in at least 0.038% (1/2653). Further, large-scale genetic studies will be needed to clarify the real prevalence of LQTS by gene carrier status, since the present study may have underestimated it.
-
1.93Impact points
Locomotor activity, ultrasonic vocalization and oxytocin levels in infant CD38 knockout mice.
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.
Following (15)
-
Hiroshi Okamoto
Mie University -
Orest Hurko
Biologics Consulting Group, Inc. -
Satoshi Ichikawa
Hokkaido University -
Hirokazu Hirai
Gunma University -
Yasuomi Ouchi
Hamamatsu University School of Medicine
Topics (1)
