27 results on '"Itohara, Shigeyoshi"'
Search Results
2. Impaired Dendritic Development and Memory inSorbs2Knock-Out Mice
- Author
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Zhang, Qiangge, primary, Gao, Xian, additional, Li, Chenchen, additional, Feliciano, Catia, additional, Wang, Dongqing, additional, Zhou, Dingxi, additional, Mei, Yuan, additional, Monteiro, Patricia, additional, Anand, Michelle, additional, Itohara, Shigeyoshi, additional, Dong, Xiaowei, additional, Fu, Zhanyan, additional, and Feng, Guoping, additional
- Published
- 2016
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3. Developmental RacGAP α2-Chimaerin Signaling Is a Determinant of the Morphological Features of Dendritic Spines in Adulthood
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Iwata, Ryohei, primary, Matsukawa, Hiroshi, additional, Yasuda, Kosuke, additional, Mizuno, Hidenobu, additional, Itohara, Shigeyoshi, additional, and Iwasato, Takuji, additional
- Published
- 2015
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4. Spinal Glutamatergic Neurons Defined by EphA4 Signaling Are Essential Components of Normal Locomotor Circuits
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Borgius, Lotta, primary, Nishimaru, Hiroshi, additional, Caldeira, Vanessa, additional, Kunugise, Yuka, additional, Löw, Peter, additional, Reig, Ramon, additional, Itohara, Shigeyoshi, additional, Iwasato, Takuji, additional, and Kiehn, Ole, additional
- Published
- 2014
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5. Impaired Dendritic Development and Memory in Sorbs2 Knock-Out Mice.
- Author
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Qiangge Zhang, Xian Gao, Chenchen Li, Feliciano, Catia, Dongqing Wang, Dingxi Zhou, Yuan Mei, Monteiro, Patricia, Anand, Michelle, Itohara, Shigeyoshi, Xiaowei Dong, Zhanyan Fu, and Guoping Feng
- Subjects
INTELLECTUAL disabilities ,DENDRITIC spines ,DENTATE gyrus ,DELETION mutation ,NEURAL transmission - Abstract
Intellectual disability is a common neurodevelopmental disorder characterized by impaired intellectual and adaptive functioning. Both environmental insults and genetic defects contribute to the etiology of intellectual disability. Copy number variations of SORBS2 have been linked to intellectual disability. However, the neurobiological function of SORBS2 in the brain is unknown. The SORBS2 gene encodes ArgBP2 (Arg/c-Abl kinase binding protein 2) protein in non-neuronal tissues and is alternatively spliced in the brain to encode nArgBP2 protein. We found nArgBP2 colocalized with F-actin at dendritic spines and growth cones in cultured hippocampal neurons. In the mouse brain, nArgBP2 was highly expressed in the cortex, amygdala, and hippocampus, and enriched in the outer one-third of the molecular layer in dentate gyrus. Genetic deletion of Sorbs2 in mice led to reduced dendritic complexity and decreased frequency of AMPAR-miniature spontaneous EPSCs in dentate gyrus granule cells. Behavioral characterization revealed that Sorbs2 deletion led to a reduced acoustic starde response, and defective long-term object recognition memory and contextual fear memory. Together, our findings demonstrate, for the first time, an important role for nArgBP2 in neuronal dendritic development and excitatory synaptic transmission, which may thus inform exploration of neurobiological basis of SORBS2 deficiency in intellectual disability. [ABSTRACT FROM AUTHOR]
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- 2016
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6. X11-Like Protein Deficiency Is Associated with Impaired Conflict Resolution in Mice
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Sano, Yoshitake, primary, Ornthanalai, Veravej G., additional, Yamada, Kazuyuki, additional, Homma, Chihiro, additional, Suzuki, Hitomi, additional, Suzuki, Toshiharu, additional, Murphy, Niall P., additional, and Itohara, Shigeyoshi, additional
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- 2009
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7. DSCAM Deficiency Causes Loss of Pre-Inspiratory Neuron Synchroneity and Perinatal Death
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Amano, Kenji, primary, Fujii, Morimitsu, additional, Arata, Satoru, additional, Tojima, Takuro, additional, Ogawa, Masaharu, additional, Morita, Noriyuki, additional, Shimohata, Atsushi, additional, Furuichi, Teiichi, additional, Itohara, Shigeyoshi, additional, Kamiguchi, Hiroyuki, additional, Korenberg, Julie R., additional, Arata, Akiko, additional, and Yamakawa, Kazuhiro, additional
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- 2009
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8. Extracellular Signal-Regulated Kinase 2 (ERK2) Knockdown Mice Show Deficits in Long-Term Memory; ERK2 Has a Specific Function in Learning and Memory
- Author
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Satoh, Yasushi, primary, Endo, Shogo, additional, Ikeda, Toshio, additional, Yamada, Kazuyuki, additional, Ito, Masataka, additional, Kuroki, Masahiko, additional, Hiramoto, Takeshi, additional, Imamura, Osamu, additional, Kobayashi, Yasushi, additional, Watanabe, Yasuhiro, additional, Itohara, Shigeyoshi, additional, and Takishima, Kunio, additional
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- 2007
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9. Netrin-G/NGL Complexes Encode Functional Synaptic Diversification.
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Matsukawa, Hiroshi, Akiyoshi-Nishimura, Sachiko, Zhang, Qi, Lujan, Rafael, Yamaguchi, Kazuhiko, Goto, Hiromichi, Yaguchi, Kunio, Hashikawa, Tsutomu, Sano, Chie, Shigemoto, Ryuichi, Nakashiba, Toshiaki, and Itohara, Shigeyoshi
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CELL adhesion molecules ,NEUROPLASTICITY ,NETRINS ,LABORATORY mice ,NEURAL transmission ,CELLULAR signal transduction - Abstract
Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and NGL-KO mice to reveal that netrin-G1/ NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampalpathways. In the hippocampal CA1 area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain how synaptic inputs are diversified to control neuronal activity. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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10. Lesion-Induced Thalamocortical Axonal Plasticity in the S1 Cortex Is Independent of NMDA Receptor Function in Excitatory Cortical Neurons
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Datwani, Akash, primary, Iwasato, Takuji, additional, Itohara, Shigeyoshi, additional, and Erzurumlu, Reha S., additional
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- 2002
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11. Protective Role of Phosphorylation in Turnover of Glial Fibrillary Acidic Protein in Mice
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Takemura, Masaaki, primary, Gomi, Hiroshi, additional, Colucci-Guyon, Emma, additional, and Itohara, Shigeyoshi, additional
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- 2002
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12. Netrin-G1: a Novel Glycosyl Phosphatidylinositol-Linked Mammalian Netrin That Is Functionally Divergent from Classical Netrins
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Nakashiba, Toshiaki, primary, Ikeda, Toshio, additional, Nishimura, Sachiko, additional, Tashiro, Kei, additional, Honjo, Tasuku, additional, Culotti, Joseph G., additional, and Itohara, Shigeyoshi, additional
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- 2000
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13. Learning Induces a CDC2-Related Protein Kinase, KKIAMRE
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Gomi, Hiroshi, primary, Sun, William, additional, Finch, Caleb E., additional, Itohara, Shigeyoshi, additional, Yoshimi, Kenji, additional, and Thompson, Richard F., additional
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- 1999
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14. Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus.
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Mizoguchi, Hiroyuki, Nakade, Junya, Tachibana, Masaki, Ibi, Daisuke, Someya, Eiichi, Koike, Hiroyuki, Kamei, Hiroyuki, Nabeshima, Toshitaka, Itohara, Shigeyoshi, Takuma, Kazuhiro, Sawada, Makoto, Sato, Jun, and Yamada, Kiyofumi
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SPASM treatment ,METALLOPROTEINASES ,STIMULANTS ,GROWTH factors ,HIPPOCAMPUS (Brain) ,DIAZEPAM ,LABORATORY mice - Abstract
The article focuses on a study related to treatment of seizures with pentylenetetrazole (PTZ) by converting pro-Brain derived neurotrophic factor (BDNF) to mature BDNF in the hippocampus. It says that repeated administration of PTZ causes matrix metalloproteinase-9 (MMP-9) expression in the hippocampus of kindled and cognitively impaired mice. It also says that pretreatment with diazepam and MK-801 inhibits PTZ induced kindled seizures and MMP-9 expression.
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- 2011
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15. NMDA Receptors in Hippocampal GABAergic Synapses and Their Role in Nitric Oxide Signaling.
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Szabadits, Eszter, Cserép, Csaba, Szõnyi, András, Fukazawa, Yugo, Shigemoto, Ryuichi, Watanabe, Masahiko, Itohara, Shigeyoshi, Freund, Tamás F., and Nyiri, Gábor
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NITRIC oxide ,NEURAL circuitry ,ACETOLACTATE synthase ,IMMUNOGOLD labeling ,LABORATORY mice ,GABA - Abstract
GABAergic inhibition plays a central role in the control of pyramidal cell ensemble activities; thus, any signaling mechanism that regulates inhibition is able to fine-tune network patterns. Here, we provide evidence that the retrograde nitric oxide (NO)-cGMP cascade triggered by NMDAreceptor(NMDAR)activation plays a role in the control of hippocampal GABAergic transmission in mice. GABAergic synapses express neuronal nitric oxide synthase (nNOS) postsynaptically and NO receptors (NO-sensitive guanylyl cyclase) in the presynaptic terminals. We hypothesized that-similar to glutamatergic synapses-the Ca
2+ transients required to activate nNOS were provided by NMDA receptor activation. Indeed, administration of 5 μM NMDA induced a robust nNOS-dependent cGMP production in GABAergic terminals, selectively in the CA1 and CA3c areas. Furthermore, using preembedding, postembedding, and SDS-digested freeze-fracture replica immunogold labeling, we provided quantitative immunocytochemical evidence that NMDAR subunits GluN1, GluN2A, and GluN2B were present in most somatic GABAergic synapses postsynaptically. These data indicate that NMDARs can modulate hippocampal GABAergic inhibition viaNO-cGMPsignaling in an activity-dependent manner and that this effect is subregion specific in the mouse hippocampus. [ABSTRACT FROM AUTHOR]- Published
- 2011
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16. Neural-Activity-Dependent Release of S100B from Astrocytes Enhances Kainate-Induced Gamma Oscillations In Vivo.
- Author
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Sakatani, Seiichi, Seto-Ohshima, Akiko, Shinohara, Yoshiaki, Yamamoto, Yasuhiko, Yamamoto, Hiroshi, Itohara, Shigeyoshi, and Hirase, Hajime
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ASTROCYTES ,PROTEINS ,GLUTAMIC acid ,IMMUNOGLOBULINS ,OSCILLATIONS - Abstract
S100B is the principal calcium-binding protein of astrocytes and known to be secreted to extracellular space. Although secreted S100B has been reported to promote neurite extension and cell survival via its receptor [receptor for advanced glycation end products (RAGE)], effects of extracellular S100B on neural activity have been mostly unexplored. Here, we demonstrate that secreted S100B enhances kainate-induced gamma oscillations. Local infusion of S100B in S100B(-/-) mice enhanced hippocampal kainate-induced gamma oscillations in vivo. In a complementary set of experiments, local application of anti-S100B antibody in wild-type mice attenuated the gamma oscillations. Both results indicate that the presence of extracellular S100B enhances the kainate-induced gamma oscillations. In acutely isolated hippocampal slices, kainate application increased S100B secretion in a neural-activity-dependent manner. Further pharmacological experiments revealed that S100B secretion was critically dependent on presynaptic release of neurotransmitter and activation of metabotropic glutamate receptor 3. Moreover, the kainate-induced gamma oscillations were attenuated by the genetic deletion or antibody blockade of RAGE in vivo. These results suggest RAGE activation by S100B enhances the gamma oscillations. Together, we propose a novel pathway of neuron- glia communications-astrocytic release of S100B modulates neural network activity through RAGE activation. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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17. Inducible cAMP Early Repressor Acts as a Negative Regulator for Kindling Epileptogenesis and Long-Term Fear Memory.
- Author
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Kojima, Nobuhiko, Borlikova, Gilyana, Sakamoto, Toshiro, Yamada, Kazuyuki, Ikeda, Toshio, Itohara, Shigeyoshi, Niki, Hiroaki, and Endo, Shogo
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GENE expression ,NEUROPLASTICITY ,NEUROPHYSIOLOGY ,PROTEINS ,POLYPEPTIDES - Abstract
20 Long-lasting neuronal plasticity as well as long-term memory (LTM) requires de novo synthesis of proteins through dynamic regulation of gene expression. cAMP-responsive element (CRE)-mediated gene transcription occurs in an activity-dependent manner and plays a pivotal role in neuronal plasticity and LTM in a variety of species. To study the physiological role of inducible cAMP early repressor (ICER), a CRE-mediated gene transcription repressor, in neuronal plasticity and LTM, we generated two types of ICER mutant mice: ICER-overexpressing (OE) mice and ICER-specific knock-out (KO) mice. Both ICER-OE and ICER-KO mice show no apparent abnormalities in their development and reproduction. A comprehensive battery of behavioral tests revealed no robust changes in locomotor activity, sensory and motor functions, and emotional responses in the mutant mice. However, long-term conditioned fear memory was attenuated in ICER-OE mice and enhanced in ICER-KO mice without concurrent changes in short-term fear memory. Furthermore, ICER-OE mice exhibited retardation of kindling development, whereas ICER-KO mice exhibited acceleration of kindling. These results strongly suggest that ICER negatively regulates the neuronal processes required for long-term fear memory and neuronal plasticity underlying kindling epileptogenesis, possibly through suppression of CRE-mediated gene transcription. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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18. Cortical Adenylyl Cyclase 1 Is Required for Thalamocortical Synapse Maturation and Aspects of Layer IV Barrel Development.
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Iwasato, Takuji, Inan, Melis, Kanki, Hiroaki, Erzurumlu, Reha S., Itohara, Shigeyoshi, and Crair, Michael C.
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SYNAPSES ,SENSORY neurons ,CEREBRAL cortex ,ADENYLATE cyclase ,NEURONS ,AXONS - Abstract
Experimental evidence from mutant or genetically altered mice indicates that the formation of barrels and the proper maturation of thalamocortical (TC) synapses in the primary somatosensory (barrel) cortex depend on mechanisms mediated by neural activity. Type 1 adenylyl cyclase (AC1), which catalyzes the formation of cAMP, is stimulated by increases in intracellular Ca
2+ levels in an activitydependent manner. The AC1 mutant mouse, barrelless (brl), lacks typical barrel cytoarchitecture, and displays presynaptic and postsynaptic functional defects at TC synapses. However, because AC1 is expressed throughout the trigeminal pathway, the barrel cortex phenotype of brl micemaybe a consequence of AC1 disruption in cortical or subcortical regions. To examine the role of cortical AC1 in the development of morphological barrels and TC synapses, we generated cortex-specific AC1 knock-out (CxAC1KO) mice. We found that neurons in layer IV form grossly normal barrels and TC axons fill barrel hollows in CxAC1KO mice. In addition, whisker lesion-induced critical period plasticity was not impaired in these mice. However, we found quantitative reductions in the quality of cortical barrel cytoarchitecture and dendritic asymmetry of layer IV barrel neurons in CxAC1KO mice. Electrophysiologically, CxAC1KO mice have deficits in the postsynaptic but not in the presynaptic maturation of TC synapses. These results suggest that activity-dependent postsynaptic AC1-cAMP signaling is required for functional maturation of TC synapses and the development of normal barrel cortex cytoarchitecture. They also suggest that the formation of the gross morphological features of barrels is independent of postsynaptic AC1 in the barrel cortex. [ABSTRACT FROM AUTHOR]- Published
- 2008
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19. Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation.
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Ogiwara, Ikuo, Miyamoto, Hiroyuki, Morita, Noriyuki, Atapour, Nafiseh, Mazaki, Emi, Inoue, Ikuyo, Takeuchi, Tamaki, Itohara, Shigeyoshi, Yanagawa, Yuchio, Obata, Kunihiko, Furuichi, Teiichi, Hensch, Takao K., and Yamakawa, Kazuhiro
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GENETIC mutation ,SODIUM channels ,INFANTILE spasms ,SEIZURES (Medicine) ,NEOCORTEX ,INTERNEURONS ,LABORATORY mice - Abstract
Loss-of-function mutations in human SCN1A gene encoding Na
v 1.1 are associated with a severe epileptic disorder known as severe myoclonic epilepsy in infancy. Here, we generated and characterized a knock-in mouse line with a loss-of-function nonsense mutation in the Scn1a gene. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. Immunohistochemical analyses revealed that, in the developing neocortex, Nav 1.1 was clustered predominantly at the axon initial segments of parvalbumin-positive (PV) interneurons. In heterozygous knock-in mice, trains of evoked action potentials in these fast-spiking, inhibitory cells exhibited pronounced spike amplitude decrement late in the burst. Our data indicate that Nav 1.1 plays critical roles in the spike output from PV interneurons and, furthermore, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice. [ABSTRACT FROM AUTHOR]- Published
- 2007
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20. Impaired Cerebellar Development and Function in Mice Lacking CAPS2, a Protein Involved in Neurotrophin Release. .
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Sadakata, Tetsushi, Kakegawa, Wataru, Mizoguchi, Akira, Washida, Miwa, Katoh-Semba, Ritsuko, Shutoh, Fumihiro, Okamoto, Takehito, Nakashima, Hisako, Kimura, Kazushi, Tanaka, Mika, Sekine, Yukiko, Itohara, Shigeyoshi, Yuzaki, Michisuke, Nagao, Soichi, and Furuichi, Teiichi
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CEREBELLUM ,CALMODULIN ,MICE ,PROTEINS ,MOLECULES ,NEUROTROPIN ,CELL death - Abstract
Ca
2+ -dependent activator protein for secretion 2 (CAPS2/CADPS2) is a secretory granule-associated protein that is abundant at the parallel fiber terminals of granule cells in the mouse cerebellum and is involved in the release of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), both of which are required for cerebellar development. The human homolog gene on chromosome 7 is located within susceptibility locus 1 of autism, a disease characterized by several cerebellar morphological abnormalities. Here we report that CAPS2 knock-out mice are deficient in the release of NT-3 and BDNF, and they consequently exhibit suppressed phosphorylation of Trk receptors in the cerebellum; these mice exhibit pronounced impairments in cerebellar development and functions, including neuronal survival, differentiation and migration of postmitotic granule cells, dendritogenesis of Purkinje cells, lobulation between lobules VI and VII, structure and vesicular distribution of parallel fiber--Purkinje cell synapses, paired-pulse facilitation at parallel fiber--Purkinje cell synapses, rotarod motor coordination, and eye movement plasticity in optokinetic training. Increased granule cell death of the external granular layer was noted in lobules VI-VII and IX, in which high BDNF and NT-3 levels are specifically localized during cerebellar development. Therefore, the deficiency of CAPS2 indicates that CAPS2-mediated neurotrophin release is indispensable for normal cerebellar development and functions, including neuronal differentiation and survival, morphogenesis, synaptic function, and motor leaning/control. The possible involvement of the CAPS2 gene in the cerebellar deficits of autistic patients is discussed. [ABSTRACT FROM AUTHOR]- Published
- 2007
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21. Enhancement of Haloperidol-Induced Catalepsy by GPR143, an L-Dopa Receptor, in Striatal Cholinergic Interneurons.
- Author
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Arai M, Suzuki E, Kitamura S, Otaki M, Kanai K, Yamasaki M, Watanabe M, Kambe Y, Murata K, Takada Y, Arisawa T, Kobayashi K, Tajika R, Miyazaki T, Yamaguchi M, Lazarus M, Hayashi Y, Itohara S, de Kerchove d'Exaerde A, Nawa H, Kim R, Bito H, Momiyama T, Masukawa D, and Goshima Y
- Subjects
- Humans, Mice, Male, Animals, Cricetinae, Haloperidol pharmacology, Levodopa adverse effects, Catalepsy chemically induced, CHO Cells, Cricetulus, Interneurons metabolism, Cholinergic Agents pharmacology, Eye Proteins metabolism, Membrane Glycoproteins metabolism, Antipsychotic Agents adverse effects, Parkinsonian Disorders, Receptors, Neurotransmitter
- Abstract
Dopamine neurons play crucial roles in pleasure, reward, memory, learning, and fine motor skills and their dysfunction is associated with various neuropsychiatric diseases. Dopamine receptors are the main target of treatment for neurologic and psychiatric disorders. Antipsychotics that antagonize the dopamine D2 receptor (DRD2) are used to alleviate the symptoms of these disorders but may also sometimes cause disabling side effects such as parkinsonism (catalepsy in rodents). Here we show that GPR143, a G-protein-coupled receptor for L-3,4-dihydroxyphenylalanine (L-DOPA), expressed in striatal cholinergic interneurons enhances the DRD2-mediated side effects of haloperidol, an antipsychotic agent. Haloperidol-induced catalepsy was attenuated in male Gpr143 gene -deficient ( Gpr143
-/y ) mice compared with wild-type (Wt) mice. Reducing the endogenous release of L-DOPA and preventing interactions between GPR143 and DRD2 suppressed the haloperidol-induced catalepsy in Wt mice but not Gpr143-/y mice. The phenotypic defect in Gpr143-/y mice was mimicked in cholinergic interneuron-specific Gpr143-/y ( Chat-cre;Gpr143flox/y ) mice. Administration of haloperidol increased the phosphorylation of ribosomal protein S6 at Ser240/244 in the dorsolateral striatum of Wt mice but not Chat-cre;Gpr143flox/y mice. In Chinese hamster ovary cells stably expressing DRD2, co-expression of GPR143 increased cell surface expression level of DRD2, and L-DOPA application further enhanced the DRD2 surface expression. Shorter pauses in cholinergic interneuron firing activity were observed after intrastriatal stimulation in striatal slice preparations from Chat-cre;Gpr143flox/y mice compared with those from Wt mice. Together, these findings provide evidence that GPR143 regulates DRD2 function in cholinergic interneurons and may be involved in parkinsonism induced by antipsychotic drugs., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)- Published
- 2024
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22. Impaired Dendritic Development and Memory in Sorbs2 Knock-Out Mice.
- Author
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Zhang Q, Gao X, Li C, Feliciano C, Wang D, Zhou D, Mei Y, Monteiro P, Anand M, Itohara S, Dong X, Fu Z, and Feng G
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Behavior, Animal, DNA genetics, Dendritic Spines pathology, Excitatory Postsynaptic Potentials physiology, Growth Cones pathology, Intellectual Disability genetics, Intellectual Disability pathology, Memory, Long-Term, Mice, Inbred C57BL, Mice, Knockout, Motor Activity genetics, RNA-Binding Proteins, Recognition, Psychology, Reflex, Startle genetics, Brain growth & development, Dendrites pathology, Memory, Microfilament Proteins genetics
- Abstract
Intellectual disability is a common neurodevelopmental disorder characterized by impaired intellectual and adaptive functioning. Both environmental insults and genetic defects contribute to the etiology of intellectual disability. Copy number variations of SORBS2 have been linked to intellectual disability. However, the neurobiological function of SORBS2 in the brain is unknown. The SORBS2 gene encodes ArgBP2 (Arg/c-Abl kinase binding protein 2) protein in non-neuronal tissues and is alternatively spliced in the brain to encode nArgBP2 protein. We found nArgBP2 colocalized with F-actin at dendritic spines and growth cones in cultured hippocampal neurons. In the mouse brain, nArgBP2 was highly expressed in the cortex, amygdala, and hippocampus, and enriched in the outer one-third of the molecular layer in dentate gyrus. Genetic deletion of Sorbs2 in mice led to reduced dendritic complexity and decreased frequency of AMPAR-miniature spontaneous EPSCs in dentate gyrus granule cells. Behavioral characterization revealed that Sorbs2 deletion led to a reduced acoustic startle response, and defective long-term object recognition memory and contextual fear memory. Together, our findings demonstrate, for the first time, an important role for nArgBP2 in neuronal dendritic development and excitatory synaptic transmission, which may thus inform exploration of neurobiological basis of SORBS2 deficiency in intellectual disability., Significance Statement: Copy number variations of the SORBS2 gene are linked to intellectual disability, but the neurobiological mechanisms are unknown. We found that nArgBP2, the only neuronal isoform encoded by SORBS2, colocalizes with F-actin at neuronal dendritic growth cones and spines. nArgBP2 is highly expressed in the cortex, amygdala, and dentate gyrus in the mouse brain. Genetic deletion of Sorbs2 in mice leads to impaired dendritic complexity and reduced excitatory synaptic transmission in dentate gyrus granule cells, accompanied by behavioral deficits in acoustic startle response and long-term memory. This is the first study of Sorbs2 function in the brain, and our findings may facilitate the study of neurobiological mechanisms underlying SORBS2 deficiency in the development of intellectual disability., (Copyright © 2016 the authors 0270-6474/16/362248-14$15.00/0.)
- Published
- 2016
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23. Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice.
- Author
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Takahashi A, Lee RX, Iwasato T, Itohara S, Arima H, Bettler B, Miczek KA, and Koide T
- Subjects
- Aggression drug effects, Animals, Baclofen administration & dosage, Baclofen pharmacology, Dorsal Raphe Nucleus drug effects, Dorsal Raphe Nucleus metabolism, Dose-Response Relationship, Drug, Glutamic Acid metabolism, Glutamic Acid pharmacology, Male, Mice, Mice, Knockout, Microinjections, Prefrontal Cortex metabolism, Receptors, GABA-B genetics, Serotonergic Neurons drug effects, Serotonergic Neurons metabolism, Serotonergic Neurons physiology, gamma-Aminobutyric Acid metabolism, Aggression physiology, Dorsal Raphe Nucleus physiology, Glutamic Acid physiology
- Abstract
Although the dorsal raphe nucleus (DRN) has long been linked to neural control of aggression, little is known about the regulatory influences of the DRN when an animal engages in either adaptive species-typical aggressive behavior or escalated aggression. Therefore it is important to explore which neurotransmitter inputs into the DRN determine the escalation of aggression in male mice. Previously, we observed that microinjection of the GABAB receptor agonist baclofen into the DRN escalates aggressive behavior in male mice. Here, we used a serotonin (5-HT) neuron-specific GABAB receptor knock-out mouse to demonstrate that baclofen acts on nonserotonergic neurons to escalate aggression. Intra-DRN baclofen administration increased glutamate release, but did not alter GABA release, within the DRN. Microinjection of l-glutamate into the DRN escalated dose-dependently attack bites toward an intruder. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. Finally, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase in 5-HT release was not observed when animals were engaged in species-typical aggression. In summary, glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons., (Copyright © 2015 the authors 0270-6474/15/356452-12$15.00/0.)
- Published
- 2015
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24. Thalamic NMDA receptor function is necessary for patterning of the thalamocortical somatosensory map and for sensorimotor behaviors.
- Author
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Arakawa H, Suzuki A, Zhao S, Tsytsarev V, Lo FS, Hayashi Y, Itohara S, Iwasato T, and Erzurumlu RS
- Subjects
- Animals, Evoked Potentials, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins genetics, Receptors, N-Methyl-D-Aspartate genetics, Social Behavior, Somatosensory Cortex metabolism, Thalamus physiology, Trigeminal Nuclei metabolism, Trigeminal Nuclei physiology, Vibrissae innervation, Vibrissae physiology, Connectome, Maze Learning, Nerve Tissue Proteins metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Somatosensory Cortex physiology, Thalamus metabolism, Touch Perception
- Abstract
NMDARs play a major role in patterning of topographic sensory maps in the brain. Genetic knock-out of the essential subunit of NMDARs in excitatory cortical neurons prevents whisker-specific neural pattern formation in the barrel cortex. To determine the role of NMDARs en route to the cortex, we generated sensory thalamus-specific NR1 (Grin1)-null mice (ThNR1KO). A multipronged approach, using histology, electrophysiology, optical imaging, and behavioral testing revealed that, in these mice, whisker patterns develop in the trigeminal brainstem but do not develop in the somatosensory thalamus. Subsequently, there is no barrel formation in the neocortex yet a partial afferent patterning develops. Whisker stimulation evokes weak cortical activity and presynaptic neurotransmitter release probability is also affected. We found several behavioral deficits in tasks, ranging from sensorimotor to social and cognitive. Collectively, these results show that thalamic NMDARs play a critical role in the patterning of the somatosensory thalamic and cortical maps and their impairment may lead to pronounced behavioral defects., (Copyright © 2014 the authors 0270-6474/14/3412001-14$15.00/0.)
- Published
- 2014
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25. CAPS1 deficiency perturbs dense-core vesicle trafficking and Golgi structure and reduces presynaptic release probability in the mouse brain.
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Sadakata T, Kakegawa W, Shinoda Y, Hosono M, Katoh-Semba R, Sekine Y, Sato Y, Tanaka M, Iwasato T, Itohara S, Furuyama K, Kawaguchi Y, Ishizaki Y, Yuzaki M, and Furuichi T
- Subjects
- Animals, Brain ultrastructure, Golgi Apparatus ultrastructure, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Presynaptic Terminals ultrastructure, Probability, Protein Transport genetics, Secretory Vesicles ultrastructure, Brain metabolism, Calcium-Binding Proteins deficiency, Golgi Apparatus metabolism, Nerve Tissue Proteins deficiency, Presynaptic Terminals metabolism, Secretory Vesicles metabolism
- Abstract
Ca(2+)-dependent activator protein for secretion 1 (CAPS1) plays a regulatory role in the dense-core vesicle (DCV) exocytosis pathway, but its functions at the cellular and synaptic levels in the brain are essentially unknown because of neonatal death soon after birth in Caps1 knock-out mice. To clarify the functions of the protein in the brain, we generated two conditional knock-out (cKO) mouse lines: 1) one lacking Caps1 in the forebrain; and 2) the other lacking Caps1 in the cerebellum. Both cKO mouse lines were born normally and grew to adulthood, although they showed subcellular and synaptic abnormalities. Forebrain-specific Caps1 cKO mice showed reduced immunoreactivity for the DCV marker secretogranin II (SgII) and the trans-Golgi network (TGN) marker syntaxin 6, a reduced number of presynaptic DCVs, and dilated trans-Golgi cisternae in the CA3 region. Cerebellum-specific Caps1 cKO mice had decreased immunoreactivity for SgII and brain-derived neurotrophic factor (BDNF) along the climbing fibers. At climbing fiber-Purkinje cell synapses, the number of DCVs was markedly lower and the number of synaptic vesicles was also reduced. Correspondingly, the mean amplitude of EPSCs was decreased, whereas paired-pulse depression was significantly increased. Our results suggest that loss of CAPS1 disrupts the TGN-DCV pathway, which possibly impairs synaptic transmission by reducing the presynaptic release probability.
- Published
- 2013
- Full Text
- View/download PDF
26. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.
- Author
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Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, Takeuchi T, Itohara S, Yanagawa Y, Obata K, Furuichi T, Hensch TK, and Yamakawa K
- Subjects
- Action Potentials genetics, Animals, Axons metabolism, Cell Line, Epilepsy metabolism, Humans, Interneurons metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Mutant Strains, NAV1.1 Voltage-Gated Sodium Channel, Nerve Net chemistry, Nerve Net metabolism, Nerve Tissue Proteins physiology, Sodium Channels physiology, Axons chemistry, Epilepsy genetics, Interneurons chemistry, Mutation, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neural Inhibition genetics, Parvalbumins biosynthesis, Sodium Channels genetics, Sodium Channels metabolism
- Abstract
Loss-of-function mutations in human SCN1A gene encoding Nav1.1 are associated with a severe epileptic disorder known as severe myoclonic epilepsy in infancy. Here, we generated and characterized a knock-in mouse line with a loss-of-function nonsense mutation in the Scn1a gene. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. Immunohistochemical analyses revealed that, in the developing neocortex, Nav1.1 was clustered predominantly at the axon initial segments of parvalbumin-positive (PV) interneurons. In heterozygous knock-in mice, trains of evoked action potentials in these fast-spiking, inhibitory cells exhibited pronounced spike amplitude decrement late in the burst. Our data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and, furthermore, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice.
- Published
- 2007
- Full Text
- View/download PDF
27. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states.
- Author
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Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, Mohler H, and Lüscher B
- Subjects
- Animals, Anxiety pathology, Cell Differentiation physiology, Depressive Disorder pathology, Hippocampus cytology, Hippocampus pathology, Mice, Mice, Knockout, Neurons cytology, Neurons pathology, Anxiety metabolism, Anxiety physiopathology, Depressive Disorder metabolism, Depressive Disorder physiopathology, Hippocampus metabolism, Neurons metabolism, Receptors, GABA-A metabolism
- Abstract
Stressful experiences in early life are known risk factors for anxiety and depressive illnesses, and they inhibit hippocampal neurogenesis and the expression of GABA(A) receptors in adulthood. Conversely, deficits in GABAergic neurotransmission and reduced neurogenesis are implicated in the etiology of pathological anxiety and diverse mood disorders. Mice that are heterozygous for the gamma2 subunit of GABA(A) receptors exhibit a modest functional deficit in mainly postsynaptic GABA(A) receptors that is associated with a behavioral, cognitive, and pharmacological phenotype indicative of heightened trait anxiety. Here we used cell type-specific and developmentally controlled inactivation of the gamma2 subunit gene to further analyze the mechanism and brain substrate underlying this phenotype. Heterozygous deletion of the gamma2 subunit induced selectively in immature neurons of the embryonic and adult forebrain resulted in reduced adult hippocampal neurogenesis associated with heightened behavioral inhibition to naturally aversive situations, including stressful situations known to be sensitive to antidepressant drug treatment. Reduced adult hippocampal neurogenesis was associated with normal cell proliferation, indicating a selective vulnerability of postmitotic immature neurons to modest functional deficits in gamma2 subunit-containing GABA(A) receptors. In contrast, a comparable forebrain-specific GABA(A) receptor deficit induced selectively in mature neurons during adolescence lacked neurogenic and behavioral consequences. These results suggest that modestly reduced GABA(A) receptor function in immature neurons of the developing and adult brain can serve as a common molecular substrate for deficits in adult neurogenesis and behavior indicative of anxious and depressive-like mood states.
- Published
- 2007
- Full Text
- View/download PDF
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