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Plasma concentrations of ghrelin in patients with Rett syndrome and its relationship to the clinical manifestations
Abstracts / Neuroscience Research 68S (2010) e109–e222
P1-p15 Plasma concentrations of ghrelin in patients with Rett syndrome and its relationship to the clinical manifestations Hara 1
Nishi 2 ,
Yoh 2 ,
Munetsugu , Yoshihiro Junko Ikuhiko Ohya 1 , Shinichiro Shibuya 1 , Takashi Nagamitsu 1 , Yushiro Mifune 3 , Eiichiro Tanaka 2 , Hiroshi Yamashita 1 , Hiroharu Kojima 5 , Kenji Hosoda 4 , Masayasu kangawa 4 , Toyojiro Matsuishi 1 1
Dept Pediatr, Kurume Univ, Kurume 2 Physiol, Kurume Univ, Kurume 3 Exp. Anim, Kurume Univ, Kurume 4 Dept. Biochem, NCVC, Suita 5 Life Sci Ins, Kurume Univ, Kurume Rett syndrome (RTT), which is caused by a mutation in the X-linked gene encoding the methyl-CpG binding protein 2, is a severe neuro-developmental disorder characterized by somatic growth failure following the deceleration of head growth, autistic behavior, epilepsy and gastrointestinal dysfunction. Ghrelin is an acylated peptide hormone mainly produced in the stomach. The active, acyl-form of ghrelin exerts multiple physiological functions including the stimulation of somatic growth, increasing the appetite, improving the motility of gut and decreasing the susceptibility to epileptic convulsions. Many of these functions are related to the clinical phenotypes of RTT, thus this study investigated the plasma concentrations of ghrelin in RTT patients in comparison to those in healthy controls or those in disease controls. Plasma samples of RTT, healthy and disease controls were obtained after the overnight fasting after obtaining the informed consent. The plasma concentrations of the three forms of ghrelin (octanoyl-, decanoyl- or total-ghrelin; O-, D- or T-ghrelin) were measured by the respective in-house RIA system. The plasma levels of the all three forms of ghrelin were significantly lower in the patients with RTT than in the controls. The plasma concentrations of both T- and D-ghrelin were inversely correlated to the body mass index (BMI or BMI-Z) in both RTT patients and in the healthy controls, respectively. Furthermore, the plasma T-ghrelin level was significantly lower in the RTT patients experiencing moderate to severe constipation, or an eating disturbance. These findings suggest that a state of hypoghrelinemia in RTT patients may affect or be related to some of the clinical features of this condition, including either somatic growth failure or gastrointestinal disorders.
e203
P1-p17 mRNA distribution of the thalidomide receptor, cereblon, in adult rat brain
Miho Aizawa 1 , Yuichi Abe 1 , Takumi Ito 2 , Hiroshi Handa 2 , Hiroyuki Nawa 1 1 Department of Molecular Neurobiology, Niigata University Brain Research Institute 2 Integrated Research Institute, Tokyo Institute of Technology
Thalidomide was developed and sold as a sedative or hypnotic drug but withdrawn due to teratogenicity and neuropathy. Children whose mothers took thalidomide during early pregnancy are found to have an increased incidence of autism and serotonergic abnormality. The latest study identified the thalidomide receptor being cereblon, a component of the E3 ubiquitin ligase complex. Cereblon appears to regulate the protein stability of calcium-activated potassium channels and its mutation in human is involved in autosomal recessive nonsyndromic mental retardation. To estimate the target regions of thalidomide in the central nervous system, here, we determined overall distributions of cereblon mRNA in adult rat brain and examined its expression in dopaminergic neurons and serotonergic cells. In situ hybridization reveals almost all neurons express cereblon mRNA with various intensities. In comparison, the signals in glial cells appeared to be modest or negligible. Intense mRNA signals were found in the limbic system (i.e. piriform cortex, hippocampus) and cerebellum. The signals in paraventricular nucleus, raphe nuclei, and locus ceruleus were also relatively strong. Double staining with the antibodies against tyrosine hydroxylase and tryptophan hydroxylase revealed the high expression of cereblon mRNA in noradrenergic and serotonergic cells. These results reveal a novel role of cereblon in regulating noradrenergic and serotonergic neurotransmission and functions. doi:10.1016/j.neures.2010.07.2471
P1-p18 An fMRI study of self-evaluation process in individuals with pervasive developmental disorders Tomoyo Morita 1 , Hirotaka Kosaka 2 , Daisuke N. Saito 3 , Makoto Ishitobi 2 , Toshio Munesue 4 , Shoji Itakura 5 , Masao Omori 6 , Hidehiko Okazawa 7 , Yuji Wada 2 , Norihiro Sadato 1,7 1
doi:10.1016/j.neures.2010.07.2469
P1-p16 The regulation of fetal neurogenesis via maternalfetal LIF-ACTH-LIF signaling relay pathway Eriko Simamura 1 , Hiroki Shimada 1 , Nobuaki Higashi 1 , Maimi Uchishiba 1 , Hiroki Otani 2 , Toshihisa Hatta 1
National Institute for Physiological Sciences, Okazaki 2 Faculty of Medical Sciences, University of Fukui, Fukui 3 Research and Education Program for Life Science, University of Fukui, Fukui 4 Research Center for Child Mental Development, Kanazawa University, Ishikawa 5 Graduate School of Letters, Kyoto University, Kyoto 6 Faculty of Nursing and Social Welfare Sciences, Fukui prefectural University, Fukui 7 Biological Imaging Research Center, University of Fukui, Fukui
1
Dept. Anatomy 1, Kanazawa Medical University, Ishikawa 2 Dept. Developmental Biology, Faculty of Medicine, Shimane Medical University, Shimane Our previous study revealed that the maternal LIF signal is transmitted to the fetus, which in turn promotes the proliferation of neuronal progenitor cells in the cerebrum in rats. However, it remains unclear how fetal LIF level is regulated. In the present study, chronological changes in rats showed that LIF concentration in fetal sera (FS) and fetal cerebrospinal fluid (CSF) peaked at 15.5 days post coitus (dpc), following the peak of maternal LIF at 14.5 dpc. LIF injection into rat dams at 15.5 dpc, increased the level of adrenocorticotropic hormone (ACTH) in FS and subsequently increased LIF levels in FS and fetal CSF. Following, an injection of recombinant LIF into rat dams at 15.5 dpc, the ACTH concentration in FS increased significantly after 30 min, and Pomc expression in the placenta was induced at 1 h. Furthermore, the LIF concentration in FS and fetal CSF increased 2.5 h later than the ACTH peak in FS. Twenty-four hours after LIF injection into dams at 12.5, 14.5 and 16.5 dpc, the BrdU-labeling index in the ventricular zone of the cerebral neocortex increased significantly at 15.5 dpc, but not at 13.5 or 17.5 dpc. These results suggested that in rats maternal LIF induces ACTH from the placenta, which in turn induces fetal LIF that eventually increases neurogenesis in fetuses around 15 dpc. This is the first model for a maternal-fetal signaling relay pathway via the placenta which contributes to the fetal brain development. It could be also designated as a model for the hypothesis that the maternal physiological condition closely relates to the fetal development. Specifically, when a mother is undernourished or there is an imbalance of hormones or cytokines, the offspring has a possibility of diathesis such as nervous developmental disability after birth, which is advocated as the hypothesis of the developmental origin of health and diseases (DOHaD). doi:10.1016/j.neures.2010.07.2470
Previous behavioral studies have suggested that individuals with pervasive developmental disorders (PDD) often showed atypical emotional response associated with intrapersonal self-referential processing, but little is known about neural mechanisms of self-referential processing in PDD. Here, we used functional MRI (fMRI) to investigate brain activity when 15 individuals with high-functioning PDD and 15 age- and IQ-matched control participants engaged in face-evaluation task. They were asked to rate images of their own face and those of others according to how photogenic they appeared to be. After the fMRI session, the participants rated how embarrassed they felt upon viewing each face. In the control group, as the photogenic rating decreased, the embarrassment ratings dramatically increased for the participant’s own face. In contrast, such relation was not obvious in the PDD group, suggesting their small variation in emotional response for own faces. Furthermore, the small variation in emotional response was associated with reduced response in insular cortex, even though the insula activity was not related to Autism-Spectrum Quotient (AQ), a measure of autistic traits. In addition, individuals with PDD showed reduced activation in cingulate cortex and right somatosensory cortex regardless of whether the target face was own or others’, and the activities were negatively correlated with the AQ. This hypoactivation might be related to less attention to own inner states. Thus, our data provide evidence that individuals with PDD would have deficits in emotional and attentional aspects of self-referential processing. doi:10.1016/j.neures.2010.07.2472
P1-p15 Plasma concentrations of ghrelin in patients with Rett syndrome and its relationship to the clinical manifestations Hara 1
Nishi 2 ,
Yoh 2 ,
Munetsugu , Yoshihiro Junko Ikuhiko Ohya 1 , Shinichiro Shibuya 1 , Takashi Nagamitsu 1 , Yushiro Mifune 3 , Eiichiro Tanaka 2 , Hiroshi Yamashita 1 , Hiroharu Kojima 5 , Kenji Hosoda 4 , Masayasu kangawa 4 , Toyojiro Matsuishi 1 1
Dept Pediatr, Kurume Univ, Kurume 2 Physiol, Kurume Univ, Kurume 3 Exp. Anim, Kurume Univ, Kurume 4 Dept. Biochem, NCVC, Suita 5 Life Sci Ins, Kurume Univ, Kurume Rett syndrome (RTT), which is caused by a mutation in the X-linked gene encoding the methyl-CpG binding protein 2, is a severe neuro-developmental disorder characterized by somatic growth failure following the deceleration of head growth, autistic behavior, epilepsy and gastrointestinal dysfunction. Ghrelin is an acylated peptide hormone mainly produced in the stomach. The active, acyl-form of ghrelin exerts multiple physiological functions including the stimulation of somatic growth, increasing the appetite, improving the motility of gut and decreasing the susceptibility to epileptic convulsions. Many of these functions are related to the clinical phenotypes of RTT, thus this study investigated the plasma concentrations of ghrelin in RTT patients in comparison to those in healthy controls or those in disease controls. Plasma samples of RTT, healthy and disease controls were obtained after the overnight fasting after obtaining the informed consent. The plasma concentrations of the three forms of ghrelin (octanoyl-, decanoyl- or total-ghrelin; O-, D- or T-ghrelin) were measured by the respective in-house RIA system. The plasma levels of the all three forms of ghrelin were significantly lower in the patients with RTT than in the controls. The plasma concentrations of both T- and D-ghrelin were inversely correlated to the body mass index (BMI or BMI-Z) in both RTT patients and in the healthy controls, respectively. Furthermore, the plasma T-ghrelin level was significantly lower in the RTT patients experiencing moderate to severe constipation, or an eating disturbance. These findings suggest that a state of hypoghrelinemia in RTT patients may affect or be related to some of the clinical features of this condition, including either somatic growth failure or gastrointestinal disorders.
e203
P1-p17 mRNA distribution of the thalidomide receptor, cereblon, in adult rat brain
Miho Aizawa 1 , Yuichi Abe 1 , Takumi Ito 2 , Hiroshi Handa 2 , Hiroyuki Nawa 1 1 Department of Molecular Neurobiology, Niigata University Brain Research Institute 2 Integrated Research Institute, Tokyo Institute of Technology
Thalidomide was developed and sold as a sedative or hypnotic drug but withdrawn due to teratogenicity and neuropathy. Children whose mothers took thalidomide during early pregnancy are found to have an increased incidence of autism and serotonergic abnormality. The latest study identified the thalidomide receptor being cereblon, a component of the E3 ubiquitin ligase complex. Cereblon appears to regulate the protein stability of calcium-activated potassium channels and its mutation in human is involved in autosomal recessive nonsyndromic mental retardation. To estimate the target regions of thalidomide in the central nervous system, here, we determined overall distributions of cereblon mRNA in adult rat brain and examined its expression in dopaminergic neurons and serotonergic cells. In situ hybridization reveals almost all neurons express cereblon mRNA with various intensities. In comparison, the signals in glial cells appeared to be modest or negligible. Intense mRNA signals were found in the limbic system (i.e. piriform cortex, hippocampus) and cerebellum. The signals in paraventricular nucleus, raphe nuclei, and locus ceruleus were also relatively strong. Double staining with the antibodies against tyrosine hydroxylase and tryptophan hydroxylase revealed the high expression of cereblon mRNA in noradrenergic and serotonergic cells. These results reveal a novel role of cereblon in regulating noradrenergic and serotonergic neurotransmission and functions. doi:10.1016/j.neures.2010.07.2471
P1-p18 An fMRI study of self-evaluation process in individuals with pervasive developmental disorders Tomoyo Morita 1 , Hirotaka Kosaka 2 , Daisuke N. Saito 3 , Makoto Ishitobi 2 , Toshio Munesue 4 , Shoji Itakura 5 , Masao Omori 6 , Hidehiko Okazawa 7 , Yuji Wada 2 , Norihiro Sadato 1,7 1
doi:10.1016/j.neures.2010.07.2469
P1-p16 The regulation of fetal neurogenesis via maternalfetal LIF-ACTH-LIF signaling relay pathway Eriko Simamura 1 , Hiroki Shimada 1 , Nobuaki Higashi 1 , Maimi Uchishiba 1 , Hiroki Otani 2 , Toshihisa Hatta 1
National Institute for Physiological Sciences, Okazaki 2 Faculty of Medical Sciences, University of Fukui, Fukui 3 Research and Education Program for Life Science, University of Fukui, Fukui 4 Research Center for Child Mental Development, Kanazawa University, Ishikawa 5 Graduate School of Letters, Kyoto University, Kyoto 6 Faculty of Nursing and Social Welfare Sciences, Fukui prefectural University, Fukui 7 Biological Imaging Research Center, University of Fukui, Fukui
1
Dept. Anatomy 1, Kanazawa Medical University, Ishikawa 2 Dept. Developmental Biology, Faculty of Medicine, Shimane Medical University, Shimane Our previous study revealed that the maternal LIF signal is transmitted to the fetus, which in turn promotes the proliferation of neuronal progenitor cells in the cerebrum in rats. However, it remains unclear how fetal LIF level is regulated. In the present study, chronological changes in rats showed that LIF concentration in fetal sera (FS) and fetal cerebrospinal fluid (CSF) peaked at 15.5 days post coitus (dpc), following the peak of maternal LIF at 14.5 dpc. LIF injection into rat dams at 15.5 dpc, increased the level of adrenocorticotropic hormone (ACTH) in FS and subsequently increased LIF levels in FS and fetal CSF. Following, an injection of recombinant LIF into rat dams at 15.5 dpc, the ACTH concentration in FS increased significantly after 30 min, and Pomc expression in the placenta was induced at 1 h. Furthermore, the LIF concentration in FS and fetal CSF increased 2.5 h later than the ACTH peak in FS. Twenty-four hours after LIF injection into dams at 12.5, 14.5 and 16.5 dpc, the BrdU-labeling index in the ventricular zone of the cerebral neocortex increased significantly at 15.5 dpc, but not at 13.5 or 17.5 dpc. These results suggested that in rats maternal LIF induces ACTH from the placenta, which in turn induces fetal LIF that eventually increases neurogenesis in fetuses around 15 dpc. This is the first model for a maternal-fetal signaling relay pathway via the placenta which contributes to the fetal brain development. It could be also designated as a model for the hypothesis that the maternal physiological condition closely relates to the fetal development. Specifically, when a mother is undernourished or there is an imbalance of hormones or cytokines, the offspring has a possibility of diathesis such as nervous developmental disability after birth, which is advocated as the hypothesis of the developmental origin of health and diseases (DOHaD). doi:10.1016/j.neures.2010.07.2470
Previous behavioral studies have suggested that individuals with pervasive developmental disorders (PDD) often showed atypical emotional response associated with intrapersonal self-referential processing, but little is known about neural mechanisms of self-referential processing in PDD. Here, we used functional MRI (fMRI) to investigate brain activity when 15 individuals with high-functioning PDD and 15 age- and IQ-matched control participants engaged in face-evaluation task. They were asked to rate images of their own face and those of others according to how photogenic they appeared to be. After the fMRI session, the participants rated how embarrassed they felt upon viewing each face. In the control group, as the photogenic rating decreased, the embarrassment ratings dramatically increased for the participant’s own face. In contrast, such relation was not obvious in the PDD group, suggesting their small variation in emotional response for own faces. Furthermore, the small variation in emotional response was associated with reduced response in insular cortex, even though the insula activity was not related to Autism-Spectrum Quotient (AQ), a measure of autistic traits. In addition, individuals with PDD showed reduced activation in cingulate cortex and right somatosensory cortex regardless of whether the target face was own or others’, and the activities were negatively correlated with the AQ. This hypoactivation might be related to less attention to own inner states. Thus, our data provide evidence that individuals with PDD would have deficits in emotional and attentional aspects of self-referential processing. doi:10.1016/j.neures.2010.07.2472