Takayoshi Mamiya

Publications of Takayoshi Mamiya

• MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation.

  Authors: Akihiro Mouri, Aya Sasaki, Ken Watanabe, Chiharu Sogawa, Shigeo Kitayama, Takayoshi Mamiya, Yoshiaki Miyamoto, Kiyofumi Yamada, Yukihiro Noda, Toshitaka Nabeshima

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 03/2012; 32(13):4562-4580.

  The ubiquitin-proteasome system (UPS) controls the stability of most cellular proteins. The polymorphism of UPS-related genes is associated with major depression disorder, but less is known about theThe ubiquitin-proteasome system (UPS) controls the stability of most cellular proteins. The polymorphism of UPS-related genes is associated with major depression disorder, but less is known about the molecule that plays a role in depression by modulating the UPS. Melanoma antigen gene-D1 (MAGE-D1) interacts with RING E3 ubiquitin ligase and is implicated in protein degradation. MAGE-D1 may thus play an important role in the CNS via ubiquitylation. Here, we clarified a novel role of MAGE-D1 in emotional functions, namely its modulation of ubiquitylation to the serotonin transporter (SERT). The MAGE-D1 knock-out and knockdown by small interfering RNA (siRNA) in the prefrontal cortex showed depression-like behavior, such as a decrease in exploratory behavior in both the home cage and novel apparatus, a decrease in social interaction, increased immobility time during forced swimming and tail suspension, and a decrease in sucrose preference without any anxiety, or cognitive or motor dysfunction. Acute and chronic (28 d) administration of sertraline (10 mg/kg) and imipramine (20 mg/kg) reversed all or part of depression-like behavior in knock-out mice. In these mice, the serotonergic function in the prefrontal cortex and hippocampus was hypoactive, accompanied by hyperexpression of SERT attributable to a decrease in ubiquitylation. Furthermore, MAGE-D1 binds to SERT via the necdin homology domain. MAGE-D1 overexpression in cells resulted in a decrease in serotonin uptake activity and the protein level of SERT but an increase in ubiquitylated SERT. Together, the present findings suggest a novel role for MAGE-D1 in depressive behaviors: modulating SERT ubiquitylation.

• A permission system for carbapenem use reduced incidence of drug-resistant bacteria and cost of antimicrobials at a general hospital in Japan.

  Authors: Yoshiaki Ikeda, Takayoshi Mamiya, Hideki Nishiyama, Shiho Narusawa, Takenao Koseki, Akihiro Mouri, Toshitaka Nabeshima

  Nagoya journal of medical science. 02/2012; 74(1-2):93-104.

  Some drug management systems have been established in Japanese hospitals to reduce medical costs and regulate drug usage. Among the many available prescription drugs, antimicrobials should be givenSome drug management systems have been established in Japanese hospitals to reduce medical costs and regulate drug usage. Among the many available prescription drugs, antimicrobials should be given special attention because their inappropriate use often leads to sudden outbreaks of resistant bacteria. As drug specialists, pharmacists should monitor the use of all drugs, particularly antimicrobials. Carbapenems are a class of broad-spectrum antimicrobials that are widely used to treat infections worldwide. However, their inappropriate use has led to an increase in the incidence of drug-resistant bacteria and consequently, medical costs, at hospitals. To reduce inappropriate use and drug resistance, we have established a permission system to control the use of carbapenems at the Japanese Red Cross Nagoya Daiichi Hospital. In this study, we retrospectively evaluated the applicability of the new permission system compared to that of the notification system and the non control system for 14 months each. The two management systems were able to maintain total antibiotic use density and control the outbreak of drug-resistant bacteria (P. aeruginosa, E. coli, and K. pneumoniae). The number of carbapenem prescriptions was decreased dramatically when this permission system was enforced. Compared to the non control system, the cost of antimicrobials was reduced by $757,470 for the 14-month study period using the permission system. These results suggest that our system to control the use of antimicrobials can efficiently suppress the incidence of drug-resistant bacteria and medical costs at hospitals.

• Risk factors for extended-spectrum beta-lactamase-producing Escherichia coli infection in hospitalized patients.

  Authors: Yoshiaki Ikeda, Takayoshi Mamiya, Hideki Nishiyama, Takenao Koseki, Akihiro Mouri, Toshitaka Nabeshima

  Nagoya journal of medical science. 02/2012; 74(1-2):105-14.

  The incidence of nosocomial infection caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria is increasing worldwide. Infections caused by ESBL producers have been associated withThe incidence of nosocomial infection caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria is increasing worldwide. Infections caused by ESBL producers have been associated with severe adverse clinical outcomes that have led to increased mortality, prolonged hospitalization, and rising medical costs. To avoid such adverse events and ineffective treatment, an appropriate use of drugs for infectious diseases is needed. To suppress the emergence and spread of drug-resistant bacteria in hospitals, it is important to be vigilant about ESBL-producing Escherichia coli (E. coli). In this study, we examined and compared seven items in a blood test between patients with ESBL-producing E. coli and non-ESBL-producing E. coli among febrile patients. We examined the levels of serum albumin, hemoglobin, and C-reactive protein (CRP), and the numbers of leucocytes, neutrophils, lymphocytes, and platelets in blood on the day of admission, the screening day during hospitalization, and the day immediately before discharge from the hospital. There were no significant differences in clinical background characteristics between the two groups of patients. In patients with invasive infections caused by ESBL-producing E. coli, serum albumin levels and the number of lymphocytes were significantly lower than those in patients not infected with ESBL producers. These values recovered to their baseline levels on the day of hospital discharge. This retrospective study suggests that serum albumin levels and the number of lymphocytes may serve as risk factors for infection by ESBL-producing E. coli, thereby supporting the appropriate use of antimicrobials in hospitals.

• Galantamine attenuates reinstatement of cue-induced methamphetamine-seeking behavior in mice.

  Authors: Takenao Koseki, Akihiro Mouri, Shizuka Suzuki, Azusa Nakajima, Takayoshi Mamiya, Yijin Yan, Toshitaka Nabeshima

  Addiction biology. 01/2012;

  Methamphetamine (METH) dependence is becoming a serious socioeconomic health problem worldwide. The enhancement of the cholinergic nervous system is expected to greatly alleviate drug dependence. WeMethamphetamine (METH) dependence is becoming a serious socioeconomic health problem worldwide. The enhancement of the cholinergic nervous system is expected to greatly alleviate drug dependence. We investigated the effect of galantamine on the reinstatement of cue-induced METH-seeking behavior using a self-administration experiment. Treatment with galantamine (1 mg/kg, p.o.) 30 minutes before exposure to the cues suppressed the reinstatement of METH-seeking behavior. However, galantamine did not affect the cue-induced reinstatement of food-seeking behavior or locomotor activity. These results suggest that galantamine may be a candidate drug for treating relapses of METH-seeking behavior.

• Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex.

  Authors: Kazuya Toriumi, Akihiro Mouri, Shiho Narusawa, Yuki Aoyama, Natsumi Ikawa, Lingling Lu, Taku Nagai, Takayoshi Mamiya, Hyoung-Chun Kim, Toshitaka Nabeshima

  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 01/2012;

  N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDAN-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.Neuropsychopharmacology advance online publication, 18 January 2012; doi:10.1038/npp.2011.324.

• Exposure to enriched environments during adolescence prevents abnormal behaviours associated with histone deacetylation in phencyclidine-treated mice.

  Authors: Takenao Koseki, Akihiro Mouri, Takayoshi Mamiya, Yuki Aoyama, Kazuya Toriumi, Shizuka Suzuki, Azusa Nakajima, Takuma Yamada, Taku Nagai, Toshitaka Nabeshima

  The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 11/2011;

  Enriched environments (EEs) during development have been shown to influence adult behaviour. Environmental conditions during childhood may contribute to the onset and/or pathology of schizophrenia;Enriched environments (EEs) during development have been shown to influence adult behaviour. Environmental conditions during childhood may contribute to the onset and/or pathology of schizophrenia; however, it remains unclear whether EE might prevent the development of schizophrenia. Herein, we investigated the effects of EE during adolescence on phencyclidine (PCP)-induced abnormal behaviour, a proposed schizophrenic endophenotype. Male ICR mice (3 wk old) were exposed to an EE for 4 wk and then treated with PCP for 2 wk. The EE potentiated the acute PCP treatment-induced hyperlocomotion in the locomotor test and prevented chronic PCP treatment-induced impairments of social behaviour and recognition memory in the social interaction and novel object recognition tests. It also prevented the PCP-induced decrease of acetylated Lys9 in histone H3-positive cells and increase of the histone deacetylase (HDAC)5 level in the prefrontal cortex. To investigate whether the histone modification during adolescence might be critical for the effect of EE, 3-wk-old mice were first treated with sodium butyrate (SB; an HDAC inhibitor) for 4 wk and then treated with PCP for 2 wk. Chronic SB treatment during adolescence mimicked the effects of EE, including potentiation of hyperlocomotion induced by acute PCP treatment and prevention of social and cognitive impairments, decrease of acetylated Lys9 in histone H3-positive cells and increase of the HDAC5 level in the prefrontal cortex associated with chronic PCP treatment. Our results suggest that EEs prevent PCP-induced abnormal behaviour associated with histone deacetylation. EEs during childhood might prove to be a novel strategy for prophylaxis against schizophrenia.

• The antidepressant-like effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane in mice is related to changes in neuroactive steroid and monoamine levels.

  Authors: Julie Espallergues, Takayoshi Mamiya, Monique Vallée, Takenao Koseki, Toshitaka Nabeshima, Jamal Temsamani, Claude Laruelle, Tangui Maurice

  Neuropharmacology. 09/2011; 62(1):492-502.

  In the present study, we analyzed the effects of a systemic treatment with the competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor trilostane on: (i) neurosteroid and monoamine levels inIn the present study, we analyzed the effects of a systemic treatment with the competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor trilostane on: (i) neurosteroid and monoamine levels in the brain, and (ii) the antidepressant activity of steroids and antidepressants in the forced swimming test (FST). 3β-HSD converts pregnenolone (PREG) into progesterone (PROG) or dehydroepiandrosterone (DHEA) into androstenedione. These neuroactive steroids are known to regulate neurotransmitters effects in the brain, particularly glutamate, γ-aminobutyric acid (GABA) and serotonin (5-HT), with consequences on mood and depression. We previously reported that trilostane showed antidepressant-like properties in the FST and concomitantly regulated plasma adrenocorticotropin (ACTH) and corticosterone levels, markers of the stress-induced hypothalamus-pituitary-adrenal (HPA) axis activation. We here observed that adrenalectomy/castration blocked the trilostane effect, outlining the importance of peripheral steroid levels. Trilostane (25 mg/kg) decreased hippocampus PROG contents and paradoxically increased circulating PROG levels. It also increased PREG levels in the hippocampus and frontal cortex. In the FST, a co-treatment with trilostane facilitated DHEAS (5-20 mg/kg) antidepressant activity, but showed only an additive, not facilitative, effect with PREGS (10-40 mg/kg), PROG (10-40 mg/kg) or allopregnanolone (ALLO, 1-8 mg/kg). Trilostane (25 mg/kg) treatment significantly increased 5-HT and (-)-norepinephrine (NE) turnovers in the hippocampus, an effect likely related to its antidepressant action. In co-administration studies, trilostane further decreased immobility following fluoxetine (30-60 mg/kg), sertraline (20-40 mg/kg) and imipramine (20-40 mg/kg), but not desipramine (20-40 mg/kg), treatments. A significant additive effect was observed for the selective 5-HT reuptake inhibitors (SSRI) at their highest dose. This study confirmed that a systemic administration of trilostane directly affected peripheral and brain levels in neuroactive steroids and monoamine turnover, resulting in antidepressant activity. The drug could be proposed as a co-treatment with SSRI. This article is part of a Special Issue entitled 'Anxiety and Depression'.

• Xanthoceraside attenuates amyloid β peptide₂₅₋₃₅-induced learning and memory impairments in mice.

  Authors: Ping Lu, Takayoshi Mamiya, Lingling Lu, Akihiro Mouri, Takashi Ikejima, Hyoung-Chum Kim, Li-Bo Zou, Toshitaka Nabeshima

  Psychopharmacology. 07/2011; 219(1):181-90.

  In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Xanthoceraside has anti-inflammatory and antioxidativeIn Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Xanthoceraside has anti-inflammatory and antioxidative activities. However, it remains unclear whether xanthoceraside improves amyloid β (Aβ)-induced neurotoxicity. The purpose of this study was to examine the effect of xanthoceraside on behavioral impairments, inflammatory responses, and oxidative stress induced by Aβ peptide(25-35) (Aβ(25-35)) in mice. The mice were treated orally with xanthoceraside (0.02, 0.08, or 0.32 mg/kg, once daily) after the intracerebroventricular injection of Aβ(25-35) (day 0). Cognitive functions were evaluated in Y-maze (day 6) and novel object recognition tests (days 7 and 8). Inducible nitric oxide synthase (iNOS) and nitrotyrosine levels in the hippocampus were examined (day 9). The mRNA expressions of iNOS and interleukin-4 (IL-4) in the hippocampus were measured 2 h and 3 days after the Aβ(25-35) injection by real-time reverse transcription-polymerase chain reaction. Xanthoceraside significantly attenuated behavioral impairments induced by Aβ(25-35) in the Y-maze and novel object recognition tests. Repeated treatment with xanthoceraside significantly inhibited the increase in the expression of iNOS and nitrotyrosine in the hippocampus induced by Aβ(25-35), which is associated with an enhanced expression of the IL-4 mRNA. These findings suggest that xanthoceraside attenuates memory impairments through amelioration of oxidative stress and inflammatory responses induced by Aβ(25-35) and is a potential candidate for an AD treatment.

• Mouse strain differences in phencyclidine-induced behavioural changes.

  Authors: Akihiro Mouri, Takenao Koseki, Shiho Narusawa, Minae Niwa, Takayoshi Mamiya, Shin-Ichi Kano, Akira Sawa, Toshitaka Nabeshima

  The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 06/2011;

  Administration of phencyclidine (PCP) is acknowledged to generate a model of psychosis in animals. With the identification of genetic susceptibility factors for schizophrenia and bipolar disorder,Administration of phencyclidine (PCP) is acknowledged to generate a model of psychosis in animals. With the identification of genetic susceptibility factors for schizophrenia and bipolar disorder, great efforts have been made to generate genetic animal models for major mental illnesses. As these disorders are multifactorial, comparisons among drug-induced (non-genetic) and genetic models are becoming an important issue in biological psychiatry. A major barrier is that the standard mouse strain used in the generation of genetic models is C57BL/6, whereas almost all studies with PCP-induced models have utilized other strains. To fill this technical gap, we systematically compared the behavioural changes upon PCP administration in different mouse strains, including C57BL/6N, C57BL/6J, ddY, and ICR. We observed strain differences in PCP-induced hyperlocomotion and enhanced immobility in the forced swim test (ddY>C57BL/6N and 6J>ICR). In contrast, there was no strain difference in the impairment of recognition memory in the novel object recognition memory test after withdrawal of chronic PCP administration. This study provides practical guidance for comparing genetic with PCP-induced models of psychosis in C57BL/6. Furthermore, such strain differences may provide a clue to the biological mechanisms underlying PCP-induced endophenotypes possibly relevant to major mental illnesses.

• Genetic animal models of schizophrenia related with the hypothesis of abnormal neurodevelopment.

  Authors: Lingling Lu, Takayoshi Mamiya, Takenao Koseki, Akihiro Mouri, Toshitaka Nabeshima

  Biological & pharmaceutical bulletin. 01/2011; 34(9):1358-63.

  Accumulating evidence supports the existence of an overlap in genetic susceptibility with schizophrenia. Translation of human genetic mutations into animals is one of the most important strategies toAccumulating evidence supports the existence of an overlap in genetic susceptibility with schizophrenia. Translation of human genetic mutations into animals is one of the most important strategies to study the pathogenesis of schizophrenia, identify potential drug targets, and test new medicines for antipsychotic treatment. Recent discoveries of susceptibility genes for schizophrenia make the possibility to develop newer genetic mouse models based on the neurodevelopmental hypotheses of schizophrenia. Although it is not possible to mimic all schizophrenic symptoms by these animal models, the genetic mouse models based on the neurodevelopmental hypothesis are widely developed to reproduce several schizophrenia-like behavioral and biochemical changes in humans. In this mini review, we will discuss the neuropathological and behavioral manifestations of representative genetic mouse models for schizophrenia, associated with the hypothesis of abnormal neurodevelopment.

• Evaluation of object-based attention in mice.

  Authors: Tursun Alkam, Masayuki Hiramatsu, Takayoshi Mamiya, Yuki Aoyama, Atsumi Nitta, Kiyofumi Yamada, Hyoung-Chun Kim, Toshitaka Nabeshima

  Behavioural brain research. 01/2011; 220(1):185-93.

  The deficits of attention result in significant impairment in daily life, and pharmacological intervention to improve attention is the most effective treatment in clinics. However, methods which areThe deficits of attention result in significant impairment in daily life, and pharmacological intervention to improve attention is the most effective treatment in clinics. However, methods which are suitable for the large scale preclinical screening of attention-improving compounds or drugs are few in the field. In this study, we have developed object-based attention task as a simple and wherever-practical method that suitable for quick drug screening in mice. Treatment with p-chlorophenylalanine (pCPA) (200mg/kg/day, i.p.) for three consecutive days reduced the prefrontal cortical content of serotonin and dopamine, and increased turn-over of dopamine while decreasing turn-over of norepinephrine in the prefrontal cortex on day 7. Auditory attention and working memory, but not long-term object memory after a long (10 min) object (two objects)-exposure period, were impaired on day 7 after the same treatment paradigm with pCPA. Novel object recognition ability immediately (<10s) after a short (3 min) object (on two objects)-exposure period was not impaired after pCPA treatment. However, novel object recognition ability immediately (<10s) after a short (3 min), but not long (6 min), object (five objects)-exposure period was impaired after pCPA treatment. For the verification, the current task, the object-based attention task, was confirmed in an attention deficit model induced by acute phencyclidine (1mg/kg, i.p.) treatment in mice. It was implied that the object-based attention task would assist the behavioral screening process of pharmacological studies on attention-improving drugs.

• Prenatal exposure to PCP produces behavioral deficits accompanied by the overexpression of GLAST in the prefrontal cortex of postpubertal mice.

  Authors: Lingling Lu, Takayoshi Mamiya, Ping Lu, Kazuya Toriumi, Akihiro Mouri, Masayuki Hiramatsu, Li-Bo Zou, Toshitaka Nabeshima

  Behavioural brain research. 01/2011; 220(1):132-9.

  Altered glutamatergic neurotransmission in the prefrontal cortex (PFC) has been implicated in a myriad of neuropsychiatric disorders. We previously reported that prenatal exposure to PCP producedAltered glutamatergic neurotransmission in the prefrontal cortex (PFC) has been implicated in a myriad of neuropsychiatric disorders. We previously reported that prenatal exposure to PCP produced long-lasting behavioral deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors. In addition, these behavioral changes were attenuated by clozapine treatment. However, whether the prenatal exposure adversely affects pre-synaptic glutamatergic neurotransmission in postpubertal mice remains unknown. In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the impairment of cognitive and emotional behavior after prenatal PCP treatment (5mg/kg/day) from E6 to E18 in mice. The PCP-treated mice showed an impairment of recognition memory in a novel object recognition test and enhancement of immobility in a forced swimming test at 8 weeks of age. Moreover, the prenatal treatment reduced the extracellular glutamate level, but increased the expression of a glial glutamate transporter (GLAST) in the PFC. The microinjection of DL-threo-β-benzyloxyaspartate (DL-TBOA, 10 nmol/site/bilaterally), a potent blocker of glutamate transporters, reversed these behavioral deficits by enhancing the prefrontal glutamatergic neurotransmission. Taken together, prenatal exposure to PCP produced impairments of long-term memory and emotional function which are associated with abnormalities of pre-synaptic glutamate transmission in the PFC of postpubertal mice. These findings suggest the prenatal inhibition of NMDA receptor function to contribute partly to the pathophysiology of neurodevelopment-related disorders, such as schizophrenia.

• Silibinin attenuates cognitive deficits and decreases of dopamine and serotonin induced by repeated methamphetamine treatment.

  Authors: Ping Lu, Takayoshi Mamiya, Lingling Lu, Akihiro Mouri, Minae Niwa, Hyoung-Chun Kim, Li-Bo Zou, Taku Nagai, Kiyofumi Yamada, Takashi Ikejima, Toshitaka Nabeshima

  Behavioural brain research. 10/2009;

  Cognitive deficits are a core feature of patients with methamphetamine (METH) abuse. It has been reported that repeated METH treatment impairs long-term recognition memory in the novel objectCognitive deficits are a core feature of patients with methamphetamine (METH) abuse. It has been reported that repeated METH treatment impairs long-term recognition memory in the novel object recognition test (NORT) in mice. Recent studies indicate that silibinin, a flavonoid derived from the herb milk thistle, has potent neuroprotective effects in cell cultures and several animal models of neurological diseases. However, its effect on the cognitive deficit induced by METH remains unclear. In the present study, we attempt to clarify the effect of silibinin on impairments of recognition memory caused by METH in mice. Mice were co-administered silibinin with METH for 7 days and then cognitive function was assessed by NORT after 7-day withdrawal. Tissue levels of dopamine and serotonin as well as their metabolites in the prefrontal cortex and hippocampus were measured 1 day after NORT. Silibinin dose-dependently ameliorated the impairment of recognition memory caused by METH treatment in mice. Silibinin significantly attenuated the decreases in the dopamine content of the prefrontal cortex and serotonin content of the hippocampus caused by METH treatment. We also found a correlation between the recognition values and dopamine and serotonin contents of the prefrontal cortex and hippocampus. The effect of silibinin on cognitive impairment may be associated with an amelioration of decreases in dopamine and serotonin levels in the prefrontal cortex and hippocampus, respectively. These results suggest that silibinin may be useful as a pharmacological tool to investigate the mechanisms of METH-induced cognitive impairments.

• Prenatal exposure to phencyclidine produces abnormal behaviour and NMDA receptor expression in postpubertal mice.

  Authors: Lingling Lu, Takayoshi Mamiya, Ping Lu, Kazuya Toriumi, Akihiro Mouri, Masayuki Hiramatsu, Hyoung-Chun Kim, Li-Bo Zou, Taku Nagai, Toshitaka Nabeshima

  The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 10/2009;

  Several studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists on neurobehavioural development. Based on the neurodevelopment hypothesis ofSeveral studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists on neurobehavioural development. Based on the neurodevelopment hypothesis of schizophrenia, there is growing interest in animal models treated with NMDA antagonists at developing stages to investigate the pathogenesis of psychological disturbances in humans. Previous studies have reported that perinatal treatment with phencyclidine (PCP) impairs the development of neuronal systems and induces schizophrenia-like behaviour. However, the adverse effects of prenatal exposure to PCP on behaviour and the function of NMDA receptors are not well understood. This study investigated the long-term effects of prenatal exposure to PCP in mice. The prenatal PCP-treated mice showed hypersensitivity to a low dose of PCP in locomotor activity and impairment of recognition memory in the novel object recognition test at age 7 wk. Meanwhile, the prenatal exposure reduced the phosphorylation of NR1, although it increased the expression of NR1 itself. Furthermore, these behavioural changes were attenuated by atypical antipsychotic treatment. Taken together, prenatal exposure to PCP produced long-lasting behavioural deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors in postpubertal mice. It is worth investigating the influences of disrupted NMDA receptors during the prenatal period on behaviour in later life.

• Silibinin attenuates amyloid {beta}25-35 peptide-induced memory impairments: Implication of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-{alpha}) in mice.

  Authors: Ping Lu, Takayoshi Mamiya, Lingling Lu, Akihiro Mouri, Minae Niwa, Masayuki Hiramatsu, Li-Bo Zou, Takashi Ikejima, Taku Nagai, Toshitaka Nabeshima

  The Journal of pharmacology and experimental therapeutics. 08/2009;

  In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milkIn Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milk thistle, has potent anti-inflammatory and antioxidant activities. However, it remains unclear whether silibinin improves amyloid beta (Abeta) peptide-induced neurotoxicity. In this study, we examined the effect of silibinin on the fear-conditioning memory deficits, inflammatory response and oxidative stress induced by the intracerebroventricular injection of Abeta peptide25-35 (Abeta25-35) in mice. Mice were treated with silibinin (2, 20, 200 mg/kg, p.o., once a day for 8 days) from the day of the Abeta25-35 injection (day 0). Memory function was evaluated in cued and contextual fear-conditioning tests (day 6). Nitrotyrosine levels in the hippocampus and amygdala were examined (day 8). The mRNA expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus and amygdala was measured 2 hours after the Abeta25-35 injection. We found that silibinin significantly attenuated memory deficits caused by Abeta25-35 in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by Abeta25-35. Nitrotyrosine levels in these regions were negatively correlated with memory performance. Moreover, real-time RT-PCR revealed that silibinin inhibited the overexpression of iNOS and TNF-alpha mRNA in the hippocampus and amygdala induced by Abeta25-35. These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by Abeta25-35 and (ii) may be a potential candidate for an AD medication.

• Usp46 is a quantitative trait gene regulating mouse immobile behavior in the tail suspension and forced swimming tests.

  Authors: Shigeru Tomida, Takayoshi Mamiya, Hirotake Sakamaki, Masami Miura, Toshihiko Aosaki, Masao Masuda, Minae Niwa, Tsutomu Kameyama, Junya Kobayashi, Yuka Iwaki, Saki Imai, Akira Ishikawa, Kuniya Abe, Takashi Yoshimura, Toshitaka Nabeshima, Shizufumi Ebihara

  Nature genetics. 06/2009;

  The tail suspension test (TST) and forced swimming test (FST) are widely used for assessing antidepressant activity and depression-like behavior. We found that CS mice show negligible immobility inThe tail suspension test (TST) and forced swimming test (FST) are widely used for assessing antidepressant activity and depression-like behavior. We found that CS mice show negligible immobility in inescapable situations. Quantitative trait locus (QTL) mapping using CS and C57BL/6J mice revealed significant QTLs on chromosomes 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on chromosome 5, we narrowed the QTL interval to 0.5 Mb using several congenic and subcongenic strains. Ubiquitin-specific peptidase 46 (Usp46) with a lysine codon deletion was located in this region. This deletion affected nest building, muscimol-induced righting reflex and anti-immobility effects of imipramine. The muscimol-induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase were significantly decreased in the Usp46 mutant mice compared to control mice. These phenotypes were rescued in transgenic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects the immobility in the TST and FST, and it is implicated in the regulation of GABA action.

• The long-lasting effects of cross-fostering on the emotional behavior in ICR mice.

  Authors: Lingling Lu, Takayoshi Mamiya, Ping Lu, Minae Niwa, Akihiro Mouri, Li-Bo Zou, Taku Nagai, Masayuki Hiramatsu, Toshitaka Nabeshima

  Behavioural brain research. 12/2008;

  Early-life stress during the postnatal period could precipitate long-lasting alterations in the functional properties underlying emotional expression in humans, but how the psychological stress ofEarly-life stress during the postnatal period could precipitate long-lasting alterations in the functional properties underlying emotional expression in humans, but how the psychological stress of cross-fostering affects emotional behavior during adulthood in mice remains primarily unknown. The purpose of the present study was to examine the long-term effects of cross-fostering on the emotional behavior and cognitive functions of ICR offspring in adulthood. Cross-fostering was performed from postnatal day 7 for 3 weeks. Mice were divided into three groups: (1) biological group: pups born from ICR dams fostered by their original mothers; (2) in-foster group: pups born from ICR dams but adopted by other ICR dams and (3) cross-foster group: ICR pups adopted by C57 dams. ICR mice were subjected to behavioral experiments at the age of 8 weeks. Emotional behaviors in the cross-fostered mice were significantly altered in the open-field, elevated plus maze and forced swimming tests, as well as social interaction test. However, the cross-fostered mice showed normal memory function in the Y-maze and novel object recognition tests. The contents of serotonin metabolisms were decreased in the prefrontal cortex and hippocampus indicated the deficit of serotoninergic neuronal function by cross-fostering. These findings suggested that the early-life stress of cross-fostering induced long-lasting emotional abnormalities, which might be possibly related to alterations of serotonin metabolisms.

• [Possible effects of ingredients in foods on brain function]

  Authors: Takayoshi Mamiya, Mitsuo Kise, Keiko Morikawa, Makoto Ukai

  Nippon yakurigaku zasshi. Folia pharmacologica Japonica. 05/2008; 131(4):244-7.

• Ferulic acid attenuated cognitive deficits and increase in carbonyl proteins induced by buthionine-sulfoximine in mice.

  Authors: Takayoshi Mamiya, Mitsuo Kise, Keiko Morikawa

  Neuroscience letters. 02/2008; 430(2):115-8.

  beta-Amyloid peptide (Abeta), the major constituent of the senile plaques observed in the brains of Alzheimer's disease patients, is cytotoxic to neurons and plays a central role in the pathogenesisbeta-Amyloid peptide (Abeta), the major constituent of the senile plaques observed in the brains of Alzheimer's disease patients, is cytotoxic to neurons and plays a central role in the pathogenesis of this disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of Abeta-induced neurotoxicity in vivo. Here, we used a mouse model of brain dysfunction induced by dl-buthionine-(S,R)-sulfoximine (BSO: 3micromol/3microL/mouse, i.c.v.), an inhibitor of glutathione synthesis. In the novel object recognition test, we found impairments of exploratory preference in the retention trial but not the training trial 24h after BSO treatment, suggesting that BSO produces cognitive dysfunction in mice. In the forebrain of this model, we observed increase in carbonyl protein levels, an index of biochemical oxidative damage of proteins, compared to vehicle-treated mice. Pretreatment with ferulic acid (5mg/kg, s.c.) once a day for 6 days inhibited the induction of deficits in memory and increase in carbonyl protein levels by BSO. These findings suggest that pretreatment with FA may attenuate the memory deficits and increase the carbonyl protein levels induced by BSO in mice.

• Intake of fermented soybean (natto) increased locomotor activity in mice.

  Authors: Takayoshi Mamiya, Atsuhisa Nishimura

  Biological & pharmaceutical bulletin. 05/2007; 30(4):845-6.

  We fed mice food granules containing fermented soybean (natto in Japanese) powder (hereafter "natto granules") for 14 d to investigate whether natto granules had any effects on mouse behavior. WeWe fed mice food granules containing fermented soybean (natto in Japanese) powder (hereafter "natto granules") for 14 d to investigate whether natto granules had any effects on mouse behavior. We noted an enhancement of locomotor activity in natto-granule-fed mice compared to control and soybean-pellet-fed mice. This enhanced locomotor activity was blocked by a low dose of haloperidol (1 microg/kg i.p.), a dopamine receptor antagonist, but not by methysergide, a serotonin 5-HT(1/2) receptor antagonist. The results suggest that the enhanced locomotor activity induced by continuous intake of natto granules in mice is sensitive to haloperidol.