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Daisuke Ibi,
Taku Nagai,
Akira Nakajima,
Hiroyuki Mizoguchi,
Takahiro Kawase,
Daisuke Tsuboi,
Shin-Ichi Kano,
Yoshiaki Sato,
Masahiro Hayakawa,
Ulrike C Lange,
David J Adams,
M Azim Surani,
Takaya Satoh,
Akira Sawa,
Kozo Kaibuchi,
Toshitaka Nabeshima,
Kiyofumi Yamada
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ABSTRACT: Interferon-induced transmembrane protein 3 (IFITM3) ıplays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long-lasting neuronal impairments in mice following polyriboinosinic-polyribocytidylic acid (polyI:C, a synthetic double-stranded RNA)-induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C-treated astrocytes (polyI:C-ACM), neurite development was impaired. These polyI:C-ACM-induced neurodevelopmental abnormalities were alleviated by ifitm3(-) (/) (-) astrocyte-conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C-treated wild-type mice, but such neuronal impairments were not observed in ifitm3(-) (/) (-) mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes. GLIA 2013.
Glia 02/2013; · 4.82 Impact Factor
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ABSTRACT: PURPOSE: 1-bromopropane (1-BP) intoxication is associated with depression and cognitive and memory deficits. The present study tested the hypothesis that 1-BP suppresses neurogenesis in the dentate gyrus, which is involved in higher cerebral function, in adult rats. METHODS: Four groups of 12 male Wistar rats were exposed to 0, 400, 800, 1000ppm 1-BP, 8hrs/day for 7 days. Another four groups of six rats each were exposed to 0, 400, 800 and 1000ppm 1-BP for 2 weeks followed by 0, 200, 400 and 800ppm for another 2 weeks, respectively. Another four groups of six rats each were exposed to 0, 200, 400 and 800ppm 1-BP for 4 weeks. Rats were injected with 5-bromo-2'-deoxy-uridine (BrdU) after 4-week exposure at 1000/800ppm to examine neurogenesis in the dentate gyrus by immunostaining. We measured factors known to affect neurogenesis, including monoamine levels, and mRNA expression levels of brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR), in different brain regions. RESULTS: BrdU-positive cells were significantly lower in the 800/1000 ppm-4-week group than the control. One-week exposure to 1-BP at 800 and 1000ppm significantly reduced noradrenalin level in the striatum. Four-week exposure at 800ppm significantly decreased noradrenalin levels in the hippocampus, prefrontal cortex and striatum. 1-BP also reduced hippocampal BDNF and GR mRNA levels. CONCLUSION: Long-term exposure to 1-BP decreased neurogenesis in the dentate gyrus. Downregulation of BDNF and GR mRNA expression and low hippocampal norepinephrine levels might contribute, at least in part, to the reduced neurogenesis.
Toxicology 12/2012; · 3.68 Impact Factor
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ABSTRACT: Schizophrenia is a severe and common psychiatric disease with a lifetime prevalence of 0.5% to 1% globally. Because of limitations of the experimental approach in humans, valid animal models are essential in the effort to identify novel therapeutics for schizophrenia. In most animal models of schizophrenia, second generation antipsychotic drugs are reported to be effective in ameliorating behavioral abnormalities, while clinical evidence indicates that some of the patients are resistant to the antipsychotic drug therapy. Accordingly, animal models of antipsychotic drug-resistant schizophrenia are needed for screening of novel agents that may be more effective than the existing antipsychotic drugs. Furthermore, utilization of appropriate behavioral tasks with reference to human testing is essential to facilitate the development of novel pharmacotherapeutic approaches for the treatment in schizophrenia. Experimental data suggest that there are different types of potential candidate molecules as novel antipsychotic drugs with some therapeutic effects on negative symptoms and cognitive deficits in schizophrenia. It is proposed that to develop novel antipsychotic drugs the efficacy of potential candidate molecules should be evaluated using animal models for treatment-resistant schizophrenia with appropriate behavioral tasks in reference to human testing.
Neurobiology of Disease 11/2012; · 5.40 Impact Factor
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Kazuhiro Takuma,
Hiroyuki Mizoguchi,
Yoko Funatsu,
Yuko Kitahara, Daisuke Ibi,
Hiroyuki Kamei,
Toshio Matsuda,
Koji Koike,
Masaki Inoue,
Taku Nagai,
Kiyofumi Yamada
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ABSTRACT: We have recently found that combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and mice and that estrogen replacement and chronic treatment with Ginkgo biloba extract EGb 761 suppress the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of placental extract on the memory impairment and neuromorphological change in OVX/stress-subjected mice. Female Slc:ICR strain mice were randomly divided into four groups: vehicle-treated OVX, porcine placental extract (120 and 2160 mg/kg)-treated OVX, and sham-operated control groups. Two weeks after surgical operation, OVX mice underwent restraint stress for 21 days (6 h/day), and all animals were then subjected to a contextual fear conditioning test followed by morphological examination by Nissl staining. Placental extract was orally administered once daily until the behavioral analysis was carried out. Chronic treatment with both doses of placental extract improved the OVX/stress-induced fear memory impairment and Nissl-positive cell loss of the hippocampal CA3 region, although it did not affect the loss of bone mineral density and increase in body weight after OVX. These results have important implications for the neuroprotective and cognition-enhancing effects of placental extract in postmenopausal women.
Journal of Pharmacological Sciences 09/2012; 120(2):89-97. · 2.08 Impact Factor
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Folia Pharmacologica Japonica 04/2012; 139(4):147-51.
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ABSTRACT: Schizophrenia affects nearly 1% of the population and is clinically characterized by positive symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. affective flattening, apathy and social withdrawal) and cognitive dysfunction. Genetic susceptibility factors for schizophrenia, such as neuregulinl, dysbindin and disrupted-in-schizophrenia 1 (DISC1), have recently been reported, some of which play a role in neurodevelopment. Furthermore, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidylic acid (polyI:C), a toll-like receptor 3 ligand, induces a strong innate immune response. Maternal immune activation by polyI:C exposure in rodents induces a wide spectrum of behavioral and neurochemical abnormalities in adult offspring. We have reported that neonatal injection of polyI:C in mice results in schizophrenia-like behavioral abnormalities in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood, by injecting polyI:C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI:C-treated DN-DISC1 mice are a validated animal model for schizophrenia with gene-environment interactions.
Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 11/2011; 31(5-6):201-7.
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Keisuke Kuroda,
Shinnosuke Yamada,
Motoki Tanaka,
Michiro Iizuka,
Hisashi Yano,
Daisuke Mori,
Daisuke Tsuboi,
Tomoki Nishioka,
Takashi Namba,
Yukihiko Iizuka, [......],
Mayu Isotani-Sakakibara,
Naoya Asai,
Kazushi Kimura,
Hiroshi Kiyonari,
Takaya Abe,
Akira Mizoguchi,
Masahiro Sokabe,
Masahide Takahashi,
Kiyofumi Yamada,
Kozo Kaibuchi
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ABSTRACT: Disrupted-In-Schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. DISC1 appears to be involved in neurogenesis, neuronal migration, axon/dendrite formation and synapse formation; during these processes, DISC1 acts as a scaffold protein by interacting with various partners. However, the lack of Disc1 knockout mice and a well-characterized antibody to DISC1 has made it difficult to determine the exact role of DISC1 in vivo. In this study, we generated mice lacking exons 2 and 3 of the Disc1 gene and prepared specific antibodies to the N- and C-termini of DISC1. The Disc1 mutant mice are viable and fertile, and no gross phenotypes, such as disorganization of the brain's cytoarchitecture, were observed. Western blot analysis revealed that the DISC1-specific antibodies recognize a protein with an apparent molecular mass of ~100 kDa in brain extracts from wild-type mice but not in brain extracts from DISC1 mutant mice. Immunochemical studies demonstrated that DISC1 is mainly localized to the vicinity of the Golgi apparatus in hippocampal neurons and astrocytes. A deficiency of full-length Disc1 induced a threshold shift in the induction of long-term potentiation in the dentate gyrus. The Disc1 mutant mice displayed abnormal emotional behavior as assessed by the elevated plus-maze and cliff-avoidance tests, thereby suggesting that a deficiency of full-length DISC1 may result in lower anxiety and/or higher impulsivity. Based on these results, we suggest that full-length Disc1-deficient mice and DISC1-specific antibodies are powerful tools for dissecting the pathophysiological functions of DISC1.
Human Molecular Genetics 09/2011; 20(23):4666-83. · 7.64 Impact Factor
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Hiroyuki Mizoguchi,
Junya Nakade,
Masaki Tachibana, Daisuke Ibi,
Eiichi Someya,
Hiroyuki Koike,
Hiroyuki Kamei,
Toshitaka Nabeshima,
Shigeyoshi Itohara,
Kazuhiro Takuma,
Makoto Sawada,
Jun Sato,
Kiyofumi Yamada
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ABSTRACT: Recurrent seizure activity has been shown to induce a variety of permanent structural changes in the brain. Matrix metalloproteinases (MMPs) function to promote neuronal plasticity, primarily through cleavage of extracellular matrix proteins. Here, we investigated the role of MMP-9 in the development of pentylenetetrazole (PTZ)-induced kindled seizure in mice. Repeated treatment with PTZ (40 mg/kg) produced kindled seizure, which was accompanied by enhanced MMP-9 activity and expression in the hippocampus. No change in MMP-9 activity was observed in the hippocampi of mice with generalized tonic seizure following single administration of PTZ (60 mg/kg). MMP-9 colocalized with the neuronal marker NeuN and the glial marker GFAP in the dentate gyrus of the kindled mouse hippocampus. Coadministration of diazepam or MK-801 with PTZ inhibited the development of kindling and the increased MMP-9 levels in the hippocampus. Marked suppression of kindled seizure progression in response to repeated PTZ treatment was observed in MMP-9((-/-)) mice compared with wild-type mice, an observation that was accompanied by decreased hippocampal levels of mature brain-derived neurotrophic factor. Microinjecting the BDNF scavenger TrkB-Fc into the right ventricle before each PTZ treatment significantly suppressed the development of kindling in wild-type mice, whereas no effect was observed in MMP-9((-/-)) mice. On the other hand, bilateral injections of pro-BDNF into the hippocampal dentate gyrus significantly enhanced kindling in wild-type mice but not MMP-9((-/-)) mice. These findings suggest that MMP-9 is involved in the progression of behavioral phenotypes in kindled mice because of conversion of pro-BDNF to mature BDNF in the hippocampus.
Journal of Neuroscience 09/2011; 31(36):12963-71. · 7.11 Impact Factor
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ABSTRACT: Interactions of environmental and genetic factors may play a role in the pathoetiology of schizophrenia. We have recently developed a novel animal model of mental disorders such as schizophrenia by inducing abnormal immune response during the perinatal period in mice with overexpression of the human dominant-negative form of disrupted-in-schizophrenia 1 (DN-DISC1). In the present study, we investigated the effects of antipsychotics on the behavioral deficits in this animal model for mental disorders with gene-environment interaction. Neonatal DN-DISC1 transgenic (DN-DISC1 tg) mice were repeatedly injected with polyriboinosinic-polyribocytidylic acid (polyI:C) for 5 days from postnatal days 2 to 6. The behavioral analyses were performed in adulthood. Clozapine (3mg/kg) or haloperidol (1mg/kg) was administered orally once a day from 1 week before starting a series of behavioral experiments and continued until the end of the study. Cognitive impairment in polyI:C-treated DN-DISC1 tg mice was improved by repeated administration of clozapine while haloperidol had no effect. Both antipsychotics suppressed the augmentation of MK-801-induced hyperactivity in the model mice. Neither clozapine nor haloperidol ameliorated the impairments of social behaviors in polyI:C-treated DN-DISC1 tg mice. These results suggest that the polyI:C-treated DN-DISC tg mice are quite unique as an animal model for mental disorders. Furthermore, this mouse model may be useful for the screening of potential antipsychotic compounds that could be more effective than clozapine in ameliorating negative symptoms and cognitive impairment in schizophrenia.
Behavioural brain research 08/2011; 225(1):305-10. · 3.22 Impact Factor
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ABSTRACT: Depression has recently become a serious problem in society worldwide. However, we lack appropriate therapeutic tools, since the causes of depression remain unclear. Degeneration of neuronal cells and a decrease in neurogenesis have been suggested recently as two of the factors responsible for depression-like behavior. Furthermore, brain-derived neurotrophic factor (BDNF) is also suggested to be an important factor in recovering from such behavior. We have previously demonstrated that the hydrophobic dipeptide leucyl-isoleucine (Leu-Ile) induces BDNF in cultured neuronal cells. We therefore investigated possible antidepressant-like effects of Leu-Ile in an animal model using the repeated forced swim test (FST). Mice were forced to swim for 6 min once a day in a cylinder containing water. The mice were treated with Leu-Ile s.c. or p.o. immediately after each FST. Five-day repeated Leu-Ile treatment significantly increased BDNF mRNA levels and activated the BDNF/Akt/mTOR signaling pathway in the hippocampi of the mice. While 2-week repeated FST increased immobility time, Leu-Ile treatment for 2 weeks offset this increase. In C57BL/6J-BDNF heterozygous knockout (BDNF(+/-)) mice, Leu-Ile failed to reduce the immobility time increased by repeated FST. We next investigated the extent of cell proliferation in the hippocampus as 5-bromo-2'-deoxy-uridine (BrdU) uptake into hippocampal cells. Repeated FST significantly reduced the number of BrdU-positive cells in the hippocampal dentate gyrus, while this deficit was prevented by repeated Leu-Ile treatment. These results suggest that Leu-Ile has an antidepressant-like effect, at least in part by supporting cell proliferation through the BDNF signaling pathway.
Behavioural brain research 02/2011; 220(2):271-80. · 3.22 Impact Factor
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ABSTRACT: Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH-treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory.
Behavioural brain research 01/2011; 220(1):159-63. · 3.22 Impact Factor
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ABSTRACT: Schizophrenia is a devastating psychiatric disorder that impairs mental and social functioning and affects approximately 1% of the population worldwide. Genetic susceptibility factors for schizophrenia have recently been reported, some of which are known to play a role in neurodevelopment; these include neuregulin-1, dysbindin, and disrupted-in-schizophrenia 1 (DISC1). Moreover, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors, especially during neurodevelopment, is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidilic acid (polyI : C) is a synthetic analogue of double-stranded RNA that leads to the pronounced but time-limited production of pro-inflammatory cytokines. Maternal immune activation by polyI : C exposure in rodents is known to precipitate a wide spectrum of behavioral, cognitive, and pharmacological abnormalities in adult offspring. Recently, we have reported that neonatal injection of polyI : C in mice results in schizophrenia-like behavioral alterations in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood by injecting polyI : C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI : C-treated DN-DISC1 mice are a well-validated animal model for schizophrenia that reflects gene-environment interactions.
Biological & Pharmaceutical Bulletin 01/2011; 34(9):1364-8. · 1.66 Impact Factor
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Jaesuk Yun,
Hiroyuki Koike, Daisuke Ibi,
Erika Toth,
Hiroyuki Mizoguchi,
Atsumi Nitta,
Masanori Yoneyama,
Kiyokazu Ogita,
Yukio Yoneda,
Toshitaka Nabeshima,
Taku Nagai,
Kiyofumi Yamada
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ABSTRACT: Neurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2'-deoxyuridine- and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosterone-induced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.
Journal of Neurochemistry 09/2010; 114(6):1840-51. · 4.06 Impact Factor
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Kazuhiro Takuma,
Fang Fang,
Wensheng Zhang,
Shiqiang Yan,
Emiko Fukuzaki,
Heng Du,
Alexander Sosunov,
Guy McKhann,
Yoko Funatsu,
Noritaka Nakamichi,
Taku Nagai,
Hiroyuki Mizoguchi, Daisuke Ibi,
Osamu Hori,
Satoshi Ogawa,
David M. Stern,
Kiyofumi Yamada,
Shirley ShiDu Yan
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ABSTRACT: Intracellular amyloid-β peptide (Aβ) has been implicated in neuronal death associated with Alzheimer's disease. Although Aβ
is predominantly secreted into the extracellular space, mechanisms of Aβ transport at the level of the neuronal cell membrane
remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport
of Aβ from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human Aβ subsequently
showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy.
Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice
displayed decreased uptake of Aβ and protection from Aβ-mediated mitochondrial dysfunction. Aβ activated p38 MAPK, but not
SAPK/JNK, and then stimulated intracellular uptake of Aβ-RAGE complex. Similar intraneuronal co-localization of Aβ and RAGE
was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate
that RAGE contributes to mechanisms involved in the translocation of Aβ from the extracellular to the intracellular space,
thereby enhancing Aβ cytotoxicity.
Proceedings of the National Academy of Sciences 11/2009; 106(47):20021-20026. · 9.68 Impact Factor
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Kazuhiro Takuma,
Fang Fang,
Wensheng Zhang,
Shiqiang Yan,
Emiko Fukuzaki,
Heng Du,
Alexander Sosunov,
Guy McKhann,
Yoko Funatsu,
Noritaka Nakamichi,
Taku Nagai,
Hiroyuki Mizoguchi, Daisuke Ibi,
Osamu Hori,
Satoshi Ogawa,
David M Stern,
Kiyofumi Yamada,
Shirley Shidu Yan
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ABSTRACT: Intracellular amyloid-beta peptide (Abeta) has been implicated in neuronal death associated with Alzheimer's disease. Although Abeta is predominantly secreted into the extracellular space, mechanisms of Abeta transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of Abeta from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human Abeta subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of Abeta and protection from Abeta-mediated mitochondrial dysfunction. Abeta activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of Abeta-RAGE complex. Similar intraneuronal co-localization of Abeta and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of Abeta from the extracellular to the intracellular space, thereby enhancing Abeta cytotoxicity.
Proceedings of the National Academy of Sciences 11/2009; 106(47):20021-6. · 9.68 Impact Factor
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ABSTRACT: Neurotransmitter release is regulated at a specific site in nerve terminals called the "active zone", which is composed of various cytomatrix proteins such as Piccolo (also known as Aczonin) and Bassoon. These proteins share regions of high sequence similarity and have very high molecular weights (>400 kDa). Since Piccolo knockout mice have not yet been established, the role of Piccolo in the neuronal system remains unclear. In this study, we investigated the effects of Piccolo antisense oligonucleotide injected into the ventricle on hippocampal long-term potentiation (LTP) and learning and memory assessed with the novel object recognition test and the Morris water maze test. There was no significant difference in cognitive memory between Piccolo antisense-treated and vehicle- or sense-treated mice; however, spatial learning in Piccolo antisense-treated mice was impaired but not in sense- or vehicle-treated mice. Next, we investigated LTP formation in these groups in area CA1 and dentate gyrus of the same hippocampal slices. The magnitude of LTP in Piccolo antisense-treated mice was significantly lower than in sense- or vehicle-treated mice, with no change in basal level. Moreover, the level of high K(+)-induced glutamate release in the antisense-treated mice was significantly lower than in sense-treated mice. Taken together, these results indicate that Piccolo plays a pivotal role in synaptic plasticity in area CA1 and in hippocampus-dependent learning in mice, and that the extracellular levels of glutamate in the hippocampus under stimulated conditions are controlled by Piccolo.
Neurochemistry International 09/2009; 56(1):77-83. · 2.86 Impact Factor
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ABSTRACT: Social isolation (SI) rearing in rodents causes a variety of behavioral changes, including hyperlocomotion, anxiety, impulsivity, aggression, and learning and memory deficits. These behavioral abnormalities in rodents may be related to the symptoms in patients with neuropsychiatric disorders, such as attention-deficit hyperactivity disorder, obsessive-compulsive disorder, autism, schizophrenia and depression. In this study, we examined the effect of long-term SI rearing after weaning on emotional behaviors and cognitive function in mice. Furthermore, the effects of methylphenidate (MPH), clozapine (CLZ) and fluoxetine (FLX) on SI-induced behavioral changes were examined to measure the predictive validity of SI-reared mice as an animal model for these neuropsychiatric disorders. MPH improved SI-induced anxiety-like behavior in the elevated-plus maze test, but had no effect on aggressive behavior. In contrast, CLZ ameliorated aggressive behavior, but not anxiety-like behavior in SI-reared mice. Repeated FLX treatment prevented SI-induced aggressive behavior and social interaction deficits. These findings suggest that SI-induced behavioral abnormality is a psychobehavioral complex relevant to various clinical symptoms observed in neuropsychiatric disorders and that SI-reared mice are a useful animal model to study the pathophysiology/pathogenesis of these diseases.
Behavioural brain research 09/2009; 202(1):114-21. · 3.22 Impact Factor
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Daisuke Ibi,
Taku Nagai,
Hiroyuki Koike,
Yuko Kitahara,
Hiroyuki Mizoguchi,
Minae Niwa,
Hanna Jaaro-Peled,
Atsumi Nitta,
Yukio Yoneda,
Toshitaka Nabeshima,
Akira Sawa,
Kiyofumi Yamada
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ABSTRACT: Gene-environment interaction may play a role in the etiology of schizophrenia. Transgenic mice expressing dominant-negative DISC1 (DN-DISC1 mice) show some histological and behavioral endophenotypes relevant to schizophrenia. Viral infection during neurodevelopment provides a major environmental risk for schizophrenia. Neonatal injection of polyriboinosinic-polyribocytidylic acid (polyI:C), which mimics innate immune responses elicited by viral infection, leads to schizophrenia-like behavioral alteration in mice after puberty. To study how gene-environmental interaction during neurodevelopment results in phenotypic changes in adulthood, we treated DN-DISC1 mice or wild-type littermates with injection of polyI:C during the neonatal stage, according to the published method, respectively, and the behavioral and histological phenotypes were examined in adulthood. We demonstrated that neonatal polyI:C treatment in DN-DISC1 mice resulted in the deficits of short-term, object recognition, and hippocampus-dependent fear memories after puberty, although polyI:C treatment by itself had smaller influences on wild-type mice. Furthermore, polyI:C-treated DN-DISC1 mice exhibited signs of impairment of social recognition and interaction, and augmented susceptibility to MK-801-induced hyperactivity as compared with vehicle-treated wild-type mice. Of most importance, additive effects of polyI:C and DN-DISC1 were observed by a marked decrease in parvalbumin-positive interneurons in the medial prefrontal cortex. These results suggest that combined effect of neonatal polyI:C treatment and DN-DISC1 affects some behavioral and histological phenotypes in adulthood.
Behavioural brain research 09/2009; 206(1):32-7. · 3.22 Impact Factor
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ABSTRACT: We have previously found that a disruption to prepulse inhibiton (PPI) induced by methamphetamine (METH) is associated with impaired functioning of pallidotegmental neurons, which play a crucial role in PPI of the startle reflex, through the activation of gamma-aminobutyric acid type B receptors in pedunculopontine tegmental neurons in mice.
Here, we examined the effect of nicotine on METH-induced impairment of PPI of the startle reflex focusing on dysfunctional pallidotegmental neurons and the neural system.
Nicotine (0.15-0.5 mg/kg) ameliorated the deficit in PPI induced by acute METH, and the ameliorating effect of nicotine was antagonized by nicotinic receptor antagonists such as methyllycaconitine and dihydro-beta-erythroidine. The acute METH-induced disruption of PPI was accompanied by suppression of c-Fos expression in the lateral globus pallidus (LGP) as well as its induction in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPI test. Nicotine-induced amelioration of PPI deficits in METH-treated mice was accompanied by a reversal of the changes in c-Fos expression in both the LGP and PnC to the basal level.
Nicotine is effective in ameliorating the impairment of PPI caused by METH, which may be associated with normalization of the pallidotegmental neurons.
Psychopharmacology 09/2009; 207(2):235-43. · 4.08 Impact Factor
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Daisuke Ibi,
Taku Nagai,
Yuko Kitahara,
Hiroyuki Mizoguchi,
Hiroyuki Koike,
Anna Shiraki,
Kazuhiro Takuma,
Hiroyuki Kamei,
Yukihiro Noda,
Atsumi Nitta,
Toshitaka Nabeshima,
Yukio Yoneda,
Kiyofumi Yamada
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ABSTRACT: It has been reported that viral infection in the first and second trimesters of pregnancy in humans increases the risk of subsequently developing schizophrenia. To develop a mouse model of immune activation during the early postnatal period, neonatal ICR mice were repeatedly injected with polyriboinosinic-polyribocytidilic acid (polyI:C; an inducer of strong innate immune responses) for 5 days (postnatal day 2-6) which may correspond, in terms of brain development, to the early second trimester in human. Cognitive and emotional behavior as well as the extracellular level of glutamate in the hippocampus were analyzed at the age of 10-12 weeks old. PolyI:C-treated mice showed anxiety-like behavior, impairment of object recognition memory and social behavior, and sensorimotor gating deficits, as compared to the saline-treated control group. Depolarization-evoked glutamate release in the hippocampus was impaired in polyI:C-treated mice compared to saline-treated control mice. Furthermore, to investigate the effect of neonatal immune activation on the expression levels of schizophrenia-related genes, we analyzed mRNA levels in the hippocampus 2 and 24h after polyI:C treatment. No significant differences or only transient and marginal changes were observed between polyI:C-treated and saline-treated control mice in the expression levels of schizophrenia-related genes in the hippocampus.
Neuroscience Research 08/2009; 64(3):297-305. · 2.25 Impact Factor
