87 results on '"Umemori H"'
Search Results
2. List of Contributors
- Author
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Abbruscato, T., primary, Al Aïn, S., additional, Alan, N., additional, Alfonso, A., additional, Ali, S.T., additional, Avila, M., additional, Barker, B.S., additional, Benedek, D.M., additional, Bizley, J.K., additional, Buffalo, E.A., additional, Cabrera, P., additional, Catani, M., additional, Cheng, J.J, additional, Chen, Y., additional, Chien, J.H., additional, Choi, K., additional, Claudio, A.O., additional, Dabrowski, A., additional, Dafny, N., additional, Dawson, M.S., additional, DeToledo, J.C., additional, El-Dokla, A.M., additional, Feroze, R.A., additional, Franklin, S., additional, Frasnelli, J.A., additional, Goodlett, C.R., additional, Gorantla, S., additional, Gulledge, A.T., additional, Hejtmancik, J.F., additional, Hoyle, J.C., additional, Hu, X.-Z., additional, Hwang, B., additional, Jennes, L., additional, Johanson, C.E., additional, Johnson, L., additional, Johnson-Venkatesh, E., additional, Julayanont, P., additional, Karatsoreos, I.N., additional, Kim, I., additional, Kim, J., additional, Koliatsos, V.E., additional, Krishnan, K.R.R., additional, Laengvejkal, P., additional, Lane, M.A., additional, Lenz, F.A., additional, Lumpkin, M.D., additional, M’Hamdi, O., additional, Mainland, J.D., additional, Meister, M.L.R., additional, Melmed, S., additional, Miller, S.L., additional, Mittleman, G., additional, Morgan, P.T., additional, Nickerson, J.M., additional, Noorani, I., additional, Okai, A., additional, Ozpinar, A., additional, Patel, M.K., additional, Pessoa, L., additional, Pollard, H., additional, Prescott, S.A., additional, Racke, M.K., additional, Ratté, S., additional, Reier, P.J., additional, Rosenfeld, G.C., additional, Rundo, J.V., additional, Ruthirago, D., additional, Ryu, J., additional, Sekula Jr., R.F., additional, Shah, K., additional, Silver, R., additional, Soubrane, C.H., additional, Stephens, G.J., additional, Stevens, E.B., additional, Swenson, R.S., additional, Tantikittichaikul, S., additional, Trimmer, C., additional, Umemori, H., additional, Ursano, R., additional, Waitzman, D.M., additional, Welch, D.M., additional, Wilms, H., additional, Wu, C.-K., additional, Wynn, G.H., additional, Xu, L., additional, Yeh, H.H., additional, Young, G.T., additional, Zhang, L., additional, Zholudeva, L.V., additional, Ziogas, N., additional, and Živković, S., additional
- Published
- 2017
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3. Synapse maturation by activity-dependent ectodomain shedding of SIRPα: S10–02
- Author
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Umemori, H.
- Published
- 2013
4. Orchestrating the synaptic network by tyrosine phosphorylation signalling
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Dabrowski, A., primary and Umemori, H., additional
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- 2011
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5. Impairment of N-methyl-d-aspartate receptor-controlled motor activity in LYN-deficient mice
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Umemori, H, primary, Ogura, H, additional, Tozawa, N, additional, Mikoshiba, K, additional, Nishizumi, H, additional, and Yamamoto, T, additional
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- 2003
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6. Physical and functional interactions of protein tyrosine kinases, p59fyn and ZAP-70, in T cell signaling.
- Author
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Fusaki, N, primary, Matsuda, S, additional, Nishizumi, H, additional, Umemori, H, additional, and Yamamoto, T, additional
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- 1996
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7. Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling.
- Author
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Tezuka, T, primary, Umemori, H, additional, Fusaki, N, additional, Yagi, T, additional, Takata, M, additional, Kurosaki, T, additional, and Yamamoto, T, additional
- Published
- 1996
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8. Identification of HS1 protein as a major substrate of protein-tyrosine kinase(s) upon B-cell antigen receptor-mediated signaling.
- Author
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Yamanashi, Y, primary, Okada, M, additional, Semba, T, additional, Yamori, T, additional, Umemori, H, additional, Tsunasawa, S, additional, Toyoshima, K, additional, Kitamura, D, additional, Watanabe, T, additional, and Yamamoto, T, additional
- Published
- 1993
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9. Distinctive roles of Fyn and Lyn in IgD- and IgM-mediated signaling
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Horikawa, K., Nishizumi, H., Umemori, H., Aizawa, S., Takatsu, K., and Yamamoto, T.
- Abstract
Src family kinases Fyn and Lyn associate with the B cell antigen receptor (BCR). Accumulating data show that Lyn plays important roles in BCR-mediated signaling, while the role of Fyn remains obscure. Here we dissected the role of Fyn and Lyn in BCR signaling using B cells from fyn-/-, lyn-/- and fyn/lyn double-deficient (fyn-/-lyn-/-) mice. In contrast to previous reports, fyn-/- B cells were slightly hyporeactive to both anti-IgM and anti-IgD-dextran. Although lyn-/- B cells were hyper-reactive to anti-IgM, anti-IgD-induced proliferation was impaired in lyn-/- B cells. Most of the other phenotypes of fyn-/-lyn-/- mice were similar to that of lyn-/- mice, except that proliferative responses of B cells to various stimuli, such as BCR cross-linking and lipopolysaccharide, were significantly lower in fyn-/-lyn-/- mice than in lyn-/- mice. Finally, immune responses to thymus-independent type 2 antigen were affected in these mutant mice. These observations suggest that Fyn and Lyn are involved in B cell functions, and play similar, but partly distinct, roles in BCR signaling.
- Published
- 1999
10. Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin.
- Author
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Hisatsune, C, Umemori, H, Inoue, T, Michikawa, T, Kohda, K, Mikoshiba, K, and Yamamoto, T
- Abstract
The N-methyl-D-aspartate (NMDA) receptor plays important roles in synaptic plasticity and brain development. The NMDA receptor subunits have large intracellular domains in the COOH-terminal region that may interact with signal-transducing proteins. By using the yeast two-hybrid system, we found that calmodulin interacts with the COOH terminus of the NR1 subunit and inactivates the channels in a Ca2+-dependent manner. Here we show that protein kinase C (PKC)-mediated phosphorylation on serine residues of NR1 decreases its affinity for calmodulin. This suggests that PKC-mediated phosphorylation of NR1 prevents calmodulin from binding to the NR1 subunit and thereby inhibits the inactivation of NMDA receptors by calmodulin. In addition, we show that stimulation of metabotropic glutamate receptor 1alpha, which potentiates NMDA channels through PKC, decreases the ability of NR1 to bind to calmodulin. Thus, our data provide clues to understanding the basis of cross-talk between two types of receptors, metabotropic glutamate receptors and the NR1 subunit, in NMDA channel potentiation.
- Published
- 1997
11. NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala
- Author
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Delawary Mina, Tezuka Tohru, Kiyama Yuji, Yokoyama Kazumasa, Inoue Takeshi, Hattori Satoko, Hashimoto Ryota, Umemori Hisashi, Manabe Toshiya, Yamamoto Tadashi, and Nakazawa Takanobu
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. There is growing evidence implicating the glutamate system in the pathophysiology and treatment of anxiety disorders, though the molecular mechanism by which the glutamate system regulates anxiety-like behavior remains unclear. Results In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to anxiety-like behavior. The GluN2B subunit of the NMDA receptor is tyrosine-phosphorylated: Tyr-1472 is the major phosphorylation site. Homozygous knock-in mice that express a Tyr-1472-Phe mutant of GluN2B, which prevents phosphorylation of this site, show enhanced anxiety-like behavior in the elevated plus-maze test. Expression of corticotropin-releasing factor (CRF), which is important for the regulation of anxiety-like behavior, is increased in the amygdala of the knock-in mice. Furthermore, injection of CRF receptor antagonist attenuated the enhanced anxiety-like behavior of the knock-in mice. We also show that elevated plus-maze exposure simultaneously induced de-phosphorylation of Tyr-1472 and increased CRF expression. Conclusions These data suggest that Tyr-1472 phosphorylation on GluN2B is important for anxiety-like behavior by negative regulation of CRF expression in the amygdala.
- Published
- 2010
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12. Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system
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Umemori, H., Wanaka, A., Kato, H., and Takeuchi, M.
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- 1992
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13. Correction: Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis.
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Dabrowski A, Terauchi A, Strong C, and Umemori H
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- 2024
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14. Shifts in receptors during submergence of an encephalitic arbovirus.
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Li W, Plante JA, Lin C, Basu H, Plung JS, Fan X, Boeckers JM, Oros J, Buck TK, Anekal PV, Hanson WA, Varnum H, Wells A, Mann CJ, Tjang LV, Yang P, Reyna RA, Mitchell BM, Shinde DP, Walker JL, Choi SY, Brusic V, Llopis PM, Weaver SC, Umemori H, Chiu IM, Plante KS, and Abraham J
- Subjects
- Animals, Female, Humans, Male, Mice, Birds metabolism, Birds virology, Communicable Diseases, Emerging epidemiology, Communicable Diseases, Emerging virology, Encephalomyelitis, Equine epidemiology, Encephalomyelitis, Equine virology, LDL-Receptor Related Proteins metabolism, Neurons metabolism, Neurons virology, Phenotype, Receptors, LDL metabolism, Receptors, LDL genetics, Viral Envelope Proteins metabolism, Viral Zoonoses epidemiology, Viral Zoonoses virology, Encephalitis Virus, Western Equine classification, Encephalitis Virus, Western Equine metabolism, Encephalitis Virus, Western Equine pathogenicity, Host Specificity, Protocadherins metabolism, Receptors, Virus metabolism
- Abstract
Western equine encephalitis virus (WEEV) is an arthropod-borne virus (arbovirus) that frequently caused major outbreaks of encephalitis in humans and horses in the early twentieth century, but the frequency of outbreaks has since decreased markedly, and strains of this alphavirus isolated in the past two decades are less virulent in mammals than strains isolated in the 1930s and 1940s
1-3 . The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity (known as viral submergence3 ) is unclear, as is the possibility of re-emergence of highly virulent strains. Here we identify protocadherin 10 (PCDH10) as a cellular receptor for WEEV. We show that multiple highly virulent ancestral WEEV strains isolated in the 1930s and 1940s, in addition to binding human PCDH10, could also bind very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), which are recognized by another encephalitic alphavirus as receptors4 . However, whereas most of the WEEV strains that we examined bind to PCDH10, a contemporary strain has lost the ability to recognize mammalian PCDH10 while retaining the ability to bind avian receptors, suggesting WEEV adaptation to a main reservoir host during enzootic circulation. PCDH10 supports WEEV E2-E1 glycoprotein-mediated infection of primary mouse cortical neurons, and administration of a soluble form of PCDH10 protects mice from lethal WEEV challenge. Our results have implications for the development of medical countermeasures and for risk assessment for re-emerging WEEV strains., (© 2024. The Author(s).)- Published
- 2024
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15. CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility.
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Awad PN, Zerbi V, Johnson-Venkatesh EM, Damiani F, Pagani M, Markicevic M, Nickles S, Gozzi A, Umemori H, and Fagiolini M
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- Animals, Mice, Male, Female, Epileptic Syndromes genetics, Epileptic Syndromes physiopathology, Gyrus Cinguli metabolism, Spasms, Infantile genetics, Spasms, Infantile physiopathology, Spasms, Infantile metabolism, Cognitive Dysfunction physiopathology, Cognitive Dysfunction genetics, Cognitive Dysfunction metabolism, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders physiopathology, Neurodevelopmental Disorders metabolism, Disease Models, Animal, Neurons metabolism, Mental Retardation, X-Linked genetics, Mental Retardation, X-Linked physiopathology, Mice, Inbred C57BL, Brain metabolism, Synapses metabolism, Synapses physiology, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Corpus Callosum metabolism, Mice, Knockout, Cognition physiology, Magnetic Resonance Imaging methods
- Abstract
Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD., (© 2023. The Author(s).)
- Published
- 2024
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16. Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.
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Barone I, Gilette NM, Hawks-Mayer H, Handy J, Zhang KJ, Chifamba FF, Mostafa E, Johnson-Venkatesh EM, Sun Y, Gibson JM, Rotenberg A, Umemori H, Tsai PT, and Lipton JO
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- Phosphorylation, Circadian Rhythm physiology, Hippocampus metabolism, ARNTL Transcription Factors genetics, Circadian Clocks
- Abstract
The time of day strongly influences adaptive behaviors like long-term memory, but the correlating synaptic and molecular mechanisms remain unclear. The circadian clock comprises a canonical transcription-translation feedback loop (TTFL) strictly dependent on the BMAL1 transcription factor. We report that BMAL1 rhythmically localizes to hippocampal synapses in a manner dependent on its phosphorylation at Ser
42 [pBMAL1(S42)]. pBMAL1(S42) regulates the autophosphorylation of synaptic CaMKIIα and circadian rhythms of CaMKIIα-dependent molecular interactions and LTP but not global rest/activity behavior. Therefore, our results suggest a model in which repurposing of the clock protein BMAL1 to synapses locally gates the circadian timing of plasticity.- Published
- 2023
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17. The projection-specific signals that establish functionally segregated dopaminergic synapses.
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Terauchi A, Yee P, Johnson-Venkatesh EM, Seiglie MP, Kim L, Pitino JC, Kritzer E, Zhang Q, Zhou J, Li Y, Ginty DD, Lee WA, and Umemori H
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- Animals, Mice, Mesencephalon, Motivation, Movement, Synapses, Corpus Striatum, Dopamine
- Abstract
Dopaminergic projections regulate various brain functions and are implicated in many neuropsychiatric disorders. There are two anatomically and functionally distinct dopaminergic projections connecting the midbrain to striatum: nigrostriatal, which controls movement, and mesolimbic, which regulates motivation. However, how these discrete dopaminergic synaptic connections are established is unknown. Through an unbiased search, we identify that two groups of antagonistic TGF-β family members, bone morphogenetic protein (BMP)6/BMP2 and transforming growth factor (TGF)-β2, regulate dopaminergic synapse development of nigrostriatal and mesolimbic neurons, respectively. Projection-preferential expression of their receptors contributes to specific synapse development. Downstream, Smad1 and Smad2 are specifically activated and required for dopaminergic synapse development and function in nigrostriatal vs. mesolimbic projections. Remarkably, Smad1 mutant mice show motor defects, whereas Smad2 mutant mice show lack of motivation. These results uncover the molecular logic underlying the proper establishment of functionally segregated dopaminergic synapses and may provide strategies to treat relevant, projection-specific disease symptoms by targeting specific BMPs/TGF-β and/or Smads., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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18. Activity-Dependent Synapse Refinement: From Mechanisms to Molecules.
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Nagappan-Chettiar S, Burbridge TJ, and Umemori H
- Abstract
The refinement of immature neuronal networks into efficient mature ones is critical to nervous system development and function. This process of synapse refinement is driven by the neuronal activity-dependent competition of converging synaptic inputs, resulting in the elimination of weak inputs and the stabilization of strong ones. Neuronal activity, whether in the form of spontaneous activity or experience-evoked activity, is known to drive synapse refinement in numerous brain regions. More recent studies are now revealing the manner and mechanisms by which neuronal activity is detected and converted into molecular signals that appropriately regulate the elimination of weaker synapses and stabilization of stronger ones. Here, we highlight how spontaneous activity and evoked activity instruct neuronal activity-dependent competition during synapse refinement. We then focus on how neuronal activity is transformed into the molecular cues that determine and execute synapse refinement. A comprehensive understanding of the mechanisms underlying synapse refinement can lead to novel therapeutic strategies in neuropsychiatric diseases characterized by aberrant synaptic function.
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- 2023
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19. The molecular signals that regulate activity-dependent synapse refinement in the brain.
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Nagappan-Chettiar S, Yasuda M, Johnson-Venkatesh EM, and Umemori H
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- Brain, Neurons physiology, Synapses physiology
- Abstract
The formation of appropriate synaptic connections is critical for the proper functioning of the brain. Early in development, neurons form a surplus of immature synapses. To establish efficient, functional neural networks, neurons selectively stabilize active synapses and eliminate less active ones. This process is known as activity-dependent synapse refinement. Defects in this process have been implicated in neuropsychiatric disorders such as schizophrenia and autism. Here we review the manner and mechanisms by which synapse elimination is regulated through activity-dependent competition. We propose a theoretical framework for the molecular mechanisms of synapse refinement, in which three types of signals regulate the refinement. We then describe the identity of these signals and discuss how multiple molecular signals interact to achieve appropriate synapse refinement in the brain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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20. ASD/OCD-Linked Protocadherin-10 Regulates Synapse, But Not Axon, Development in the Amygdala and Contributes to Fear- and Anxiety-Related Behaviors.
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Hoshina N, Johnson-Venkatesh EM, Rally VR, Sant J, Hoshina M, Seiglie MP, and Umemori H
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- Amygdala metabolism, Animals, Anxiety genetics, Anxiety psychology, Fear physiology, Humans, Male, Mice, Protocadherins, Synapses metabolism, Autism Spectrum Disorder metabolism, Obsessive-Compulsive Disorder
- Abstract
The Protocadherin-10 ( PCDH10 ) gene is associated with autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). The PCDH10 protein is a homophilic cell adhesion molecule that belongs to the δ2-protocadherin family. PCDH10 is highly expressed in the developing brain, especially in the basolateral nucleus of the amygdala (BLA). However, the role of PCDH10 in vivo has been debatable: one paper reported that a Pcdh10 mutant mouse line showed changes in axonal projections; however, another Pcdh10 mutant mouse line was reported to have failed to detect axonal phenotypes. Therefore, the actual roles of PCDH10 in the brain remain to be elucidated. We established a new Pcdh10 KO mouse line using the CRISPR/Cas9 system, without inserting gene cassettes to avoid nonspecific effects, examined the roles of PCDH10 in the brain, and studied the behavioral consequences of Pcdh10 inactivation. Here, we show that Pcdh10 KO mice do not show defects in axonal development. Instead, we find that Pcdh10 KO mice exhibit impaired development of excitatory synapses in the dorsal BLA. We further demonstrate that male Pcdh10 KO mice exhibit reduced anxiety-related behaviors, impaired fear conditioning, decreased stress-coping responses, and mildly impaired social recognition and communication. These results indicate that PCDH10 plays a critical role in excitatory synapse development, but not axon development, in the dorsal BLA and that PCDH10 regulates anxiety-related, fear-related, and stress-related behaviors. Our results reveal the roles of PCDH10 in the brain and its relationship to relevant psychiatric disorders such as ASD, OCD, and MD. SIGNIFICANCE STATEMENT Protocadherin-10 ( PCDH10 ) encodes a cell adhesion molecule and is implicated in autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). PCDH10 is highly expressed in the basolateral nucleus of the amygdala (BLA). However, the phenotypes of previously published Pcdh10 mutant mice are debatable, and some are possibly because of the nonspecific effects of the LacZ/Neo cassette inserted in the mice. We have generated a new Pcdh10 mutant mouse line without the LacZ/Neo cassette. Using our new mouse line, we reveal the roles of PCDH10 for excitatory synapse development in the BLA. The mutant mice exhibit anxiety-related, fear-related, and stress-related behaviors, which are relevant to ASD, OCD, and MD, suggesting a possible treatment strategy for such psychiatric disorders., (Copyright © 2022 the authors.)
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- 2022
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21. In utero intraocular AAV injection for early gene expression in the developing rodent retina.
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Yasuda M, Nagappan-Chettiar S, and Umemori H
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- Animals, Dependovirus genetics, Fetus surgery, Gene Expression genetics, Gene Expression Profiling methods, Gene Expression Regulation, Developmental genetics, Mice embryology, Retina growth & development, Synapses, Transcriptome genetics, Visual Pathways growth & development, Injections, Intraocular methods, Retina embryology, Transgenes genetics
- Abstract
The visual system is the best system to study activity-dependent sensory circuit development. The connections from the retina to the dorsal lateral geniculate nucleus, the retinogeniculate connections, undergo extensive remodeling during early postnatal life. Thus, techniques that allow the expression of transgenes early in the developing retina are essential to study visual system development. Here, we describe a protocol to express genes-of-interest in the developing mouse retina via in utero intraocular adeno-associated virus injections. For complete details on the use and execution of this protocol, please refer to Yasuda et al. (2021)., Competing Interests: The authors declare no competing interest., (© 2021 The Author(s).)
- Published
- 2021
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22. An activity-dependent determinant of synapse elimination in the mammalian brain.
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Yasuda M, Nagappan-Chettiar S, Johnson-Venkatesh EM, and Umemori H
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- Animals, Gyrus Cinguli metabolism, Mice, Neurons metabolism, STAT1 Transcription Factor metabolism, Signal Transduction physiology, Synapses metabolism, Gyrus Cinguli physiology, Janus Kinase 2 metabolism, Neuronal Plasticity physiology, Neurons physiology, Synapses physiology
- Abstract
To establish functional neural circuits in the brain, synaptic connections are refined by neural activity during development, where active connections are maintained and inactive ones are eliminated. However, the molecular signals that regulate synapse refinement remain to be elucidated. When we inactivate a subset of neurons in the mouse cingulate cortex, their callosal connections are eliminated through activity-dependent competition. Using this system, we identify JAK2 tyrosine kinase as a key regulator of inactive synapse elimination. We show that JAK2 is necessary and sufficient for elimination of inactive connections; JAK2 is activated at inactive synapses in response to signals from other active synapses; STAT1, a substrate of JAK2, mediates inactive synapse elimination; JAK2 signaling is critical for physiological refinement of synapses during normal development; and JAK2 regulates synapse refinement in multiple brain regions. We propose that JAK2 is an activity-dependent switch that serves as a determinant of inactive synapse elimination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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23. Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder.
- Author
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Hoshina N, Johnson-Venkatesh EM, Hoshina M, and Umemori H
- Subjects
- Animals, CA3 Region, Hippocampal physiopathology, CA3 Region, Hippocampal ultrastructure, Cadherins genetics, Cognitive Dysfunction genetics, Disease Models, Animal, Epilepsy genetics, Epilepsy physiopathology, Female, Genes, X-Linked, Genetic Diseases, X-Linked genetics, Long-Term Potentiation, Male, Mice, Mossy Fibers, Hippocampal ultrastructure, Mutation, Protocadherins, Sex Characteristics, Synapses ultrastructure, beta Catenin metabolism, Cadherins metabolism, Cognitive Dysfunction physiopathology, Genetic Diseases, X-Linked physiopathology, Mossy Fibers, Hippocampal physiopathology, Synapses physiology
- Abstract
Protocadherin-19 ( PCDH19 ) mutations cause early-onset seizures and cognitive impairment. The PCDH19 gene is on the X-chromosome. Unlike most X-linked disorders, PCDH19 mutations affect heterozygous females ( PCDH19
HET♀ ) but not hemizygous males ( PCDH19HEMI♂ ); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19HET♀ but not Pcdh19HEMI♂ mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19HET♀ but not Pcdh19HEMI♂ mice exhibit reduced pattern completion and separation abilities, which require mossy fiber synaptic function. Furthermore, PCDH19 appears to interact with N-cadherin at mossy fiber synapses. In Pcdh19HET♀ conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin-dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19HET♀ phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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24. A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding.
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Li T, Chiou B, Gilman CK, Luo R, Koshi T, Yu D, Oak HC, Giera S, Johnson-Venkatesh E, Muthukumar AK, Stevens B, Umemori H, and Piao X
- Subjects
- Animals, Mice, Mice, Transgenic, Microglia cytology, Phosphatidylserines genetics, Protein Binding, Protein Isoforms, Receptors, G-Protein-Coupled genetics, Synapses genetics, Alternative Splicing, Microglia metabolism, Phosphatidylserines metabolism, Receptors, G-Protein-Coupled metabolism, Synapses metabolism
- Abstract
Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes, remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: In neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on presynaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion of Gpr56 leads to increased synapses as a result of reduced microglial engulfment of PS
+ presynaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes., (© 2020 The Authors.)- Published
- 2020
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25. Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors.
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Luo L, Ambrozkiewicz MC, Benseler F, Chen C, Dumontier E, Falkner S, Furlanis E, Gomez AM, Hoshina N, Huang WH, Hutchison MA, Itoh-Maruoka Y, Lavery LA, Li W, Maruo T, Motohashi J, Pai EL, Pelkey KA, Pereira A, Philips T, Sinclair JL, Stogsdill JA, Traunmüller L, Wang J, Wortel J, You W, Abumaria N, Beier KT, Brose N, Burgess HA, Cepko CL, Cloutier JF, Eroglu C, Goebbels S, Kaeser PS, Kay JN, Lu W, Luo L, Mandai K, McBain CJ, Nave KA, Prado MAM, Prado VF, Rothstein J, Rubenstein JLR, Saher G, Sakimura K, Sanes JR, Scheiffele P, Takai Y, Umemori H, Verhage M, Yuzaki M, Zoghbi HY, Kawabe H, and Craig AM
- Subjects
- Animals, Female, Genes, Reporter, Germ Cells, Male, Mice, Mice, Transgenic, Mosaicism, Gene Targeting methods, Integrases genetics, Neurons metabolism, Oocytes metabolism, Recombination, Genetic genetics, Spermatozoa metabolism
- Abstract
The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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26. Neuronal fibroblast growth factor 22 signaling during development, but not in adults, is involved in anhedonia.
- Author
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Terauchi A, Durlacher E, Pitino J, and Umemori H
- Subjects
- Aging, Animals, Brain metabolism, Fibroblast Growth Factors metabolism, Mice, Transgenic, Neurogenesis physiology, Neurons metabolism, Signal Transduction physiology, Synapses metabolism, Anhedonia physiology, Brain growth & development, Fibroblast Growth Factors genetics, Neurogenesis genetics
- Abstract
Growth factor signaling in the brain is implicated in many neuropsychiatric disorders, including depression, autism, and epilepsy. Fibroblast growth factor 22 is a growth factor that regulates excitatory synapse development and neurogenesis in the brain. We have previously shown that adult mice in which fibroblast growth factor 22 is constitutively inactivated in all cells throughout life (fibroblast growth factor 22-null mice) show anhedonia, a core feature of depression in humans, suggesting that fibroblast growth factor 22 signaling contributes to the regulation of affective behavior. Here we asked (1) whether inactivation of fibroblast growth factor 22 specifically in neurons is sufficient to induce anhedonia in mice and (2) whether fibroblast growth factor 22 signaling is important during development or in adults for the regulation of affective behavior. To address these questions, we performed the sucrose preference test, which is used as an indicator of anhedonia, with neuron-specific conditional fibroblast growth factor 22 knockout mice, in which fibroblast growth factor 22 is inactivated in neurons at birth (neonatal-fibroblast growth factor 22-knockout mice) or in adults (adult-fibroblast growth factor 22-knockout mice). We found that neonatal-fibroblast growth factor 22-knockout mice show anhedonia (decreased preference for sucrose), while adult-fibroblast growth factor 22-knockout mice do not. Therefore, neuronal fibroblast growth factor 22 signaling is critical during development, and not in adults, for the regulation of affective behavior. Our work also implies that defects in growth factor-dependent synapse development, neurogenesis, or both may underlie depression of a developmental origin.
- Published
- 2020
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27. CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development.
- Author
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Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, Walker AJ, Heller MD, Umemori H, Chen C, and Stevens B
- Subjects
- Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis physiology, Receptors, Immunologic metabolism, CD47 Antigen metabolism, Microglia metabolism, Neurogenesis physiology, Neuronal Plasticity physiology, Synapses metabolism
- Abstract
Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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28. Tyrosine phosphorylation of the transmembrane protein SIRPα: Sensing synaptic activity and regulating ectodomain cleavage for synapse maturation.
- Author
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Nagappan-Chettiar S, Johnson-Venkatesh EM, and Umemori H
- Subjects
- Animals, Hippocampus cytology, Hippocampus drug effects, Hippocampus metabolism, Humans, Janus Kinases genetics, Janus Kinases metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons cytology, Neurons drug effects, Patch-Clamp Techniques, Phosphorylation, Potassium Chloride pharmacology, Primary Cell Culture, Protein Domains, Proteolysis, Receptors, Immunologic genetics, Synapses drug effects, Synaptic Transmission, Tissue Inhibitor of Metalloproteinases pharmacology, src-Family Kinases genetics, src-Family Kinases metabolism, Memory physiology, Neurons metabolism, Protein Processing, Post-Translational, Receptors, Immunologic metabolism, Synapses metabolism, Tyrosine metabolism
- Abstract
Synapse maturation is a neural activity-dependent process during brain development, in which active synapses preferentially undergo maturation to establish efficient neural circuits in the brain. Defects in this process are implicated in various neuropsychiatric disorders. We have previously reported that a postsynaptic transmembrane protein, signal regulatory protein-α (SIRPα), plays an important role in activity-dependently directing synapse maturation. In the presence of synaptic activity, the ectodomain of SIRPα is cleaved and released and then acts as a retrograde signal to induce presynaptic maturation. However, how SIRPα detects synaptic activity to promote its ectodomain cleavage and synapse maturation is unknown. Here, we show that activity-dependent tyrosine phosphorylation of SIRPα is critical for SIRPα cleavage and synapse maturation. We found that during synapse maturation and in response to neural activity, SIRPα is highly phosphorylated on its tyrosine residues in the hippocampus, a structure critical for learning and memory. Tyrosine phosphorylation of SIRPα was necessary for SIRPα cleavage and presynaptic maturation, as indicated by the fact that a phosphorylation-deficient SIRPα variant underwent much less cleavage and could not drive presynaptic maturation. However, SIRPα phosphorylation did not affect its synaptic localization. Finally, we show that inhibitors of the Src and JAK kinase family suppress neural activity-dependent SIRPα phosphorylation and cleavage. Together, our results indicate that SIRPα phosphorylation serves as a mechanism for detecting synaptic activity and linking it to the ectodomain cleavage of SIRPα, which in turn drives synapse maturation in an activity-dependent manner., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2018
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29. Selective Inactivation of Fibroblast Growth Factor 22 (FGF22) in CA3 Pyramidal Neurons Impairs Local Synaptogenesis and Affective Behavior Without Affecting Dentate Neurogenesis.
- Author
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Terauchi A, Gavin E, Wilson J, and Umemori H
- Abstract
Various growth factors regulate synapse development and neurogenesis, and are essential for brain function. Changes in growth factor signaling are implicated in many neuropsychiatric disorders such as depression, autism and epilepsy. We have previously identified that fibroblast growth factor 22 (FGF22) is critical for excitatory synapse formation in several brain regions including the hippocampus. Mice with a genetic deletion of FGF22 (FGF22 null mice) have fewer excitatory synapses in the hippocampus. We have further found that as a behavioral consequence, FGF22 null mice show a depression-like behavior phenotype such as increased passive stress-coping behavior and anhedonia, without any changes in motor, anxiety, or social cognitive tests, suggesting that FGF22 is specifically important for affective behavior. Thus, addressing the precise roles of FGF22 in the brain will help understand how synaptogenic growth factors regulate affective behavior. In the hippocampus, FGF22 is expressed mainly by CA3 pyramidal neurons, but also by a subset of dentate granule cells. We find that in addition to synapse formation, FGF22 also contributes to neurogenesis in the dentate gyrus: FGF22 null mice show decreased dentate neurogenesis. To understand the cell type-specific roles of FGF22, we generated and analyzed CA3-specific FGF22 knockout mice (FGF22-CA3KO). We show that FGF22-CA3KO mice have reduced excitatory synapses on CA3 pyramidal neurons, but do not show changes in dentate neurogenesis. Behaviorally, FGF22-CA3KO mice still show increased immobility and decreased latency to float in the forced swim test and decreased preference for sucrose in the sucrose preference test, which are suggestive of a depressive-like phenotype similar to FGF22 null mice. These results demonstrate that: (i) CA3-derived FGF22 serves as a target-derived excitatory synaptic organizer in CA3 in vivo ; (ii) FGF22 plays important roles in dentate neurogenesis, but CA3-derived FGF22 is not involved in neurogenesis; and (iii) a depression-like phenotype can result from FGF22 inactivation selectively in CA3 pyramidal neurons. Our results link the role of CA3-derived FGF22 in synapse development, and not in neurogenesis, to affective behavior.
- Published
- 2017
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30. Activity-dependent proteolytic cleavage of cell adhesion molecules regulates excitatory synaptic development and function.
- Author
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Nagappan-Chettiar S, Johnson-Venkatesh EM, and Umemori H
- Subjects
- Alzheimer Disease metabolism, Animals, Brain growth & development, Brain Neoplasms metabolism, Humans, Neuronal Plasticity, Neurons metabolism, Proteolysis, Schizophrenia metabolism, Brain physiology, Cell Adhesion Molecules metabolism, Synapses physiology
- Abstract
Activity-dependent remodeling of neuronal connections is critical to nervous system development and function. These processes rely on the ability of synapses to detect neuronal activity and translate it into the appropriate molecular signals. One way to convert neuronal activity into downstream signaling is the proteolytic cleavage of cell adhesion molecules (CAMs). Here we review studies demonstrating the mechanisms by which proteolytic processing of CAMs direct the structural and functional remodeling of excitatory glutamatergic synapses during development and plasticity. Specifically, we examine how extracellular proteolytic cleavage of CAMs switches on or off molecular signals to 1) permit, drive, or restrict synaptic maturation during development and 2) strengthen or weaken synapses during adult plasticity. We will also examine emerging studies linking improper activity-dependent proteolytic processing of CAMs to neurological disorders such as schizophrenia, brain tumors, and Alzheimer's disease. Together these findings suggest that the regulation of activity-dependent proteolytic cleavage of CAMs is vital to proper brain development and lifelong function., (Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.)
- Published
- 2017
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31. A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory.
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Mathew RS, Tatarakis A, Rudenko A, Johnson-Venkatesh EM, Yang YJ, Murphy EA, Todd TP, Schepers ST, Siuti N, Martorell AJ, Falls WA, Hammack SE, Walsh CA, Tsai LH, Umemori H, Bouton ME, and Moazed D
- Subjects
- Animals, Mice, Neurotransmitter Agents metabolism, Receptors, Glutamate metabolism, Fear, Feedback, Physiological, Hippocampus physiology, Memory, MicroRNAs metabolism, Neurons physiology, Synaptic Vesicles metabolism
- Abstract
The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway., Competing Interests: The authors declare that no competing interests exist.
- Published
- 2016
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32. Postsynaptic SDC2 induces transsynaptic signaling via FGF22 for bidirectional synaptic formation.
- Author
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Hu HT, Umemori H, and Hsueh YP
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Cell Line, Tumor, Dendritic Spines metabolism, Heparitin Sulfate metabolism, Kinesins, Mice, Models, Biological, Protein Binding, Protein Domains, Pseudopodia metabolism, Rats, Sprague-Dawley, Syndecan-2 chemistry, Fibroblast Growth Factors metabolism, Presynaptic Terminals metabolism, Signal Transduction, Syndecan-2 metabolism
- Abstract
Functional synapse formation requires tight coordination between pre- and post-synaptic termini. Previous studies have shown that postsynaptic expression of heparan sulfate proteoglycan syndecan-2 (SDC2) induces dendritic spinogenesis. Those SDC2-induced dendritic spines are frequently associated with presynaptic termini. However, how postsynaptic SDC2 accelerates maturation of corresponding presynaptic termini is unknown. Because fibroblast growth factor 22 (FGF22), a heparan sulfate binding growth factor, has been shown to act as a presynaptic organizer released from the postsynaptic site, it seems possible that postsynaptic SDC2 presents FGF22 to the presynaptic FGF receptor to promote presynaptic differentiation. Here, we show that postsynaptic SDC2 uses its ectodomain to interact with and facilitate dendritic filopodial targeting of FGF22, triggering presynaptic maturation. Since SDC2 also enhances filopodial targeting of NMDAR via interaction with the CASK-mLIN7-MINT1 adaptor complex, presynaptic maturation promoted by FGF22 further feeds back to activate NMDAR at corresponding postsynaptic sites through increased neurotransmitter release and, consequently, promotes the dendritic filopodia-spines (F-S) transition. Meanwhile, via regulation of the KIF17 motor, CaMKII (activated by the NMDAR pathway) may further facilitate FGF22 targeting to dendritic filopodia that receive presynaptic stimulation. Our study suggests a positive feedback that promotes the coordination of postsynaptic and presynaptic differentiation.
- Published
- 2016
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33. Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice.
- Author
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Williams AJ, Yee P, Smith MC, Murphy GG, and Umemori H
- Subjects
- Adaptation, Ocular genetics, Animals, Cognition physiology, Disease Models, Animal, Exploratory Behavior physiology, Female, Fibroblast Growth Factors genetics, Food Preferences physiology, Hindlimb Suspension, Immobility Response, Tonic physiology, Locomotion physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity genetics, Motor Activity physiology, Social Behavior, Sucrose administration & dosage, Swimming physiology, Swimming psychology, Depression genetics, Depression physiopathology, Fibroblast Growth Factors deficiency
- Abstract
Specific growth factors induce formation and differentiation of excitatory and inhibitory synapses, and are essential for brain development and function. Fibroblast growth factor 22 (FGF22) is important for specifying excitatory synapses during development, including in the hippocampus. Mice with a genetic deletion of FGF22 (FGF22KO) during development subsequently have fewer hippocampal excitatory synapses in adulthood. As a result, FGF22KO mice are resistant to epileptic seizure induction. In addition to playing a key role in learning, the hippocampus is known to mediate mood and anxiety. Here, we explored whether loss of FGF22 alters affective, anxiety or social cognitive behaviors in mice. We found that relative to control mice, FGF22KO mice display longer duration of floating and decreased latency to float in the forced swim test, increased immobility in the tail suspension test, and decreased preference for sucrose in the sucrose preference test, which are all suggestive of a depressive-like phenotype. No differences were observed between control and FGF22KO mice in other behavioral assays, including motor, anxiety, or social cognitive tests. These results suggest a novel role for FGF22 specifically in affective behaviors., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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34. Retrograde fibroblast growth factor 22 (FGF22) signaling regulates insulin-like growth factor 2 (IGF2) expression for activity-dependent synapse stabilization in the mammalian brain.
- Author
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Terauchi A, Johnson-Venkatesh EM, Bullock B, Lehtinen MK, and Umemori H
- Subjects
- Animals, Mice, Cell Communication, Fibroblast Growth Factors metabolism, Gene Expression Regulation, Hippocampus physiology, Insulin-Like Growth Factor II biosynthesis, Neurons physiology, Synapses physiology
- Abstract
Communication between pre- and postsynaptic cells promotes the initial organization of synaptic specializations, but subsequent synaptic stabilization requires transcriptional regulation. Here we show that fibroblast growth factor 22 (FGF22), a target-derived presynaptic organizer in the mouse hippocampus, induces the expression of insulin-like growth factor 2 (IGF2) for the stabilization of presynaptic terminals. FGF22 is released from CA3 pyramidal neurons and organizes the differentiation of excitatory nerve terminals formed onto them. Local application of FGF22 on the axons of dentate granule cells (DGCs), which are presynaptic to CA3 pyramidal neurons, induces IGF2 in the DGCs. IGF2, in turn, localizes to DGC presynaptic terminals and stabilizes them in an activity-dependent manner. IGF2 application rescues presynaptic defects of Fgf22(-/-) cultures. IGF2 is dispensable for the initial presynaptic differentiation, but is required for the following presynaptic stabilization both in vitro and in vivo. These results reveal a novel feedback signal that is critical for the activity-dependent stabilization of presynaptic terminals in the mammalian hippocampus.
- Published
- 2016
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35. Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network.
- Author
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Dabrowski A and Umemori H
- Abstract
Brain development involves multiple levels of molecular coordination in forming a functional nervous system. The hippocampus is a brain area that is important for memory formation and spatial reasoning. During early postnatal development of the hippocampal circuit, Fibroblast growth factor 22 (FGF22) and FGF7 act to establish a balance of excitatory and inhibitory tone. Both FGFs are secreted from CA3 dendrites, acting on excitatory or inhibitory axon terminals formed onto CA3 dendrites, respectively. Mechanistically, FGF22 utilizes FGFR2b and FGFR1b to induce synaptic vesicle recruitment within axons of dentate granule cells (DGCs), and FGF7 utilizes FGFR2b to induce synaptic vesicle recruitment within interneuron axons. FGF signaling eventually induces gene expression in the presynaptic neurons; however, the effects of FGF22-induced gene expression within DGCs and FGF7-induced gene expression within interneurons in the context of a developing hippocampal circuit have yet to be explored. Here, we propose one hypothetical mechanism of FGF22-induced gene expression in controlling adult neurogenesis.
- Published
- 2016
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36. Excitability governs neural development in a hippocampal region-specific manner.
- Author
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Johnson-Venkatesh EM, Khan MN, Murphy GG, Sutton MA, and Umemori H
- Subjects
- Analysis of Variance, Animals, CA1 Region, Hippocampal cytology, CA3 Region, Hippocampal cytology, Cell Count, Dendrites ultrastructure, Dentate Gyrus cytology, Immunohistochemistry, Mice, Mice, Transgenic, Microscopy, Confocal, Neurons metabolism, Pyramidal Cells cytology, Pyramidal Cells metabolism, Hippocampus embryology, Neurogenesis physiology, Neurons cytology, Synaptic Transmission physiology
- Abstract
Neuronal activity, including intrinsic neuronal excitability and synaptic transmission, is an essential regulator of brain development. However, how the intrinsic neuronal excitability of distinct neurons affects their integration into developing circuits remains poorly understood. To investigate this problem, we created several transgenic mouse lines in which intrinsic excitability is suppressed, and the neurons are effectively silenced, in different excitatory neuronal populations of the hippocampus. Here we show that CA1, CA3 and dentate gyrus neurons each have unique responses to suppressed intrinsic excitability during circuit development. Silenced CA1 pyramidal neurons show altered spine development and synaptic transmission after postnatal day 15. By contrast, silenced CA3 pyramidal neurons seem to develop normally. Silenced dentate granule cells develop with input-specific decreases in spine density starting at postnatal day 11; however, a compensatory enhancement of neurotransmitter release onto these neurons maintains normal levels of synaptic activity. The synaptic changes in CA1 and dentate granule neurons are not observed when synaptic transmission, rather than intrinsic excitability, is blocked in these neurons. Thus, our results demonstrate a crucial role for intrinsic neuronal excitability in establishing hippocampal connectivity and reveal that neuronal development in each hippocampal region is distinctly regulated by excitability., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
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37. Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis.
- Author
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Dabrowski A, Terauchi A, Strong C, and Umemori H
- Subjects
- Animals, Cell Differentiation genetics, Cell Differentiation physiology, Cells, Cultured, Fibroblast Growth Factors genetics, Fibroblast Growth Factors metabolism, Mice, Mice, Knockout, Neurogenesis genetics, Neurogenesis physiology, Neurons cytology, Neurons metabolism, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Receptors, Fibroblast Growth Factor genetics, Receptors, Fibroblast Growth Factor metabolism, Synapses metabolism
- Abstract
Neurons in the brain must establish a balanced network of excitatory and inhibitory synapses during development for the brain to function properly. An imbalance between these synapses underlies various neurological and psychiatric disorders. The formation of excitatory and inhibitory synapses requires precise molecular control. In the hippocampus, the structure crucial for learning and memory, fibroblast growth factor 22 (FGF22) and FGF7 specifically promote excitatory or inhibitory synapse formation, respectively. Knockout of either Fgf gene leads to excitatory-inhibitory imbalance in the mouse hippocampus and manifests in an altered susceptibility to epileptic seizures, underscoring the importance of FGF-dependent synapse formation. However, the receptors and signaling mechanisms by which FGF22 and FGF7 induce excitatory and inhibitory synapse differentiation are unknown. Here, we show that distinct sets of overlapping FGF receptors (FGFRs), FGFR2b and FGFR1b, mediate excitatory or inhibitory presynaptic differentiation in response to FGF22 and FGF7. Excitatory presynaptic differentiation is impaired in Fgfr2b and Fgfr1b mutant mice; however, inhibitory presynaptic defects are only found in Fgfr2b mutants. FGFR2b and FGFR1b are required for an excitatory presynaptic response to FGF22, whereas only FGFR2b is required for an inhibitory presynaptic response to FGF7. We further find that FGFRs are required in the presynaptic neuron to respond to FGF22, and that FRS2 and PI3K, but not PLCγ, mediate FGF22-dependent presynaptic differentiation. Our results reveal the specific receptors and signaling pathways that mediate FGF-dependent presynaptic differentiation, and thereby provide a mechanistic understanding of precise excitatory and inhibitory synapse formation in the mammalian brain., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
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38. FGF22 signaling regulates synapse formation during post-injury remodeling of the spinal cord.
- Author
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Jacobi A, Loy K, Schmalz AM, Hellsten M, Umemori H, Kerschensteiner M, and Bareyre FM
- Subjects
- Animals, Axons physiology, Fibroblast Growth Factors genetics, Mice, Inbred C57BL, Mice, Knockout, Nerve Regeneration physiology, Neuronal Plasticity physiology, Neurons metabolism, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Signal Transduction, Spinal Cord Injuries physiopathology, Synapses physiology, Fibroblast Growth Factors metabolism, Spinal Cord Injuries metabolism, Synapses metabolism
- Abstract
The remodeling of axonal circuits after injury requires the formation of new synaptic contacts to enable functional recovery. Which molecular signals initiate such axonal and synaptic reorganisation in the adult central nervous system is currently unknown. Here, we identify FGF22 as a key regulator of circuit remodeling in the injured spinal cord. We show that FGF22 is produced by spinal relay neurons, while its main receptors FGFR1 and FGFR2 are expressed by cortical projection neurons. FGF22 deficiency or the targeted deletion of FGFR1 and FGFR2 in the hindlimb motor cortex limits the formation of new synapses between corticospinal collaterals and relay neurons, delays their molecular maturation, and impedes functional recovery in a mouse model of spinal cord injury. These results establish FGF22 as a synaptogenic mediator in the adult nervous system and a crucial regulator of synapse formation and maturation during post-injury remodeling in the spinal cord., (© 2015 The Authors.)
- Published
- 2015
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39. Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7.
- Author
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Terauchi A, Timmons KM, Kikuma K, Pechmann Y, Kneussel M, and Umemori H
- Subjects
- Animals, Carrier Proteins metabolism, Excitatory Postsynaptic Potentials genetics, Fibroblast Growth Factor 7 genetics, Fibroblast Growth Factors genetics, Hippocampus growth & development, Humans, Kinesins metabolism, Membrane Proteins metabolism, Mice, Microtubules metabolism, Synapses physiology, Fibroblast Growth Factor 7 metabolism, Fibroblast Growth Factors metabolism, Hippocampus metabolism, Synapses metabolism
- Abstract
Specific formation of excitatory and inhibitory synapses is crucial for proper functioning of the brain. Fibroblast growth factor 22 (FGF22) and FGF7 are postsynaptic-cell-derived presynaptic organizers necessary for excitatory and inhibitory presynaptic differentiation, respectively, in the hippocampus. For the establishment of specific synaptic networks, these FGFs must localize to appropriate synaptic locations - FGF22 to excitatory and FGF7 to inhibitory postsynaptic sites. Here, we show that distinct motor and adaptor proteins contribute to intracellular microtubule transport of FGF22 and FGF7. Excitatory synaptic targeting of FGF22 requires the motor proteins KIF3A and KIF17 and the adaptor protein SAP102 (also known as DLG3). By contrast, inhibitory synaptic targeting of FGF7 requires the motor KIF5 and the adaptor gephyrin. Time-lapse imaging shows that FGF22 moves with SAP102, whereas FGF7 moves with gephyrin. These results reveal the basis of selective targeting of the excitatory and inhibitory presynaptic organizers that supports their different synaptogenic functions. Finally, we found that knockdown of SAP102 or PSD95 (also known as DLG4), which impairs the differentiation of excitatory synapses, alters FGF7 localization, suggesting that signals from excitatory synapses might regulate inhibitory synapse formation by controlling the distribution of the inhibitory presynaptic organizer., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
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40. 5-HT1A receptor-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) is modulated by regulator of G protein signaling protein 19.
- Author
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Wang Q, Terauchi A, Yee CH, Umemori H, and Traynor JR
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Adenylyl Cyclase Inhibitors, Adenylyl Cyclases metabolism, Animals, Cells, Cultured, Fibroblast Growth Factor 2 pharmacology, GTP-Binding Protein alpha Subunit, Gi2 metabolism, Humans, Mice, Mice, Inbred ICR, Phosphorylation drug effects, RGS Proteins antagonists & inhibitors, RGS Proteins genetics, RNA Interference, RNA, Small Interfering metabolism, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Signal Transduction drug effects, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, RGS Proteins metabolism, Receptor, Serotonin, 5-HT1A metabolism
- Abstract
The 5-HT1A receptor is a G protein coupled receptor (GPCR) that activates G proteins of the Gαi/o family. 5-HT1A receptors expressed in the raphe, hippocampus and prefrontal cortex are implicated in the control of mood and are targets for anti-depressant drugs. Regulators of G protein signaling (RGS) proteins are members of a large family that play important roles in signal transduction downstream of G protein coupled receptors (GPCRs). The main role of RGS proteins is to act as GTPase accelerating proteins (GAPs) to dampen or negatively regulate GPCR-mediated signaling. We have shown that a mouse expressing Gαi2 that is insensitive to all RGS protein GAP activity has an anti-depressant-like phenotype due to increased signaling of postsynaptic 5-HT1A receptors, thus implicating the 5-HT1A receptor-Gαi2 complex as an important target. Here we confirm that RGS proteins act as GAPs to regulate signaling to adenylate cyclase and the mitogen-activated protein kinase (MAPK) pathway downstream of the 5-HT1A receptor, using RGS-insensitive Gαi2 protein expressed in C6 cells. We go on to use short hairpin RNA (shRNA) to show that RGS19 is responsible for the GAP activity in C6 cells and also that RGS19 acts as a GAP for 5-HT1A receptor signaling in human neuroblastoma SH-SY5Y cells and primary hippocampal neurons. In addition, in both cell types the synergy between 5-HT1A receptor and the fibroblast growth factor receptor 1 in stimulating the MAPK pathway is enhanced following shRNA reduction of RGS19 expression. Thus RGS19 may be a viable new target for anti-depressant medications., (Copyright © 2014. Published by Elsevier Inc.)
- Published
- 2014
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41. The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease.
- Author
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Williams AJ and Umemori H
- Abstract
Growth factors play important roles in synapse formation. Mouse models of neuropsychiatric diseases suggest that defects in synaptogenic growth factors, their receptors, and signaling pathways can lead to disordered neural development and various behavioral phenotypes, including anxiety, memory problems, and social deficits. Genetic association studies in humans have found evidence for similar relationships between growth factor signaling pathways and neuropsychiatric phenotypes. Accumulating data suggest that dysfunction in neuronal circuitry, caused by defects in growth factor-mediated synapse formation, contributes to the susceptibility to multiple neuropsychiatric diseases, including epilepsy, autism, and disorders of thought and mood (e.g., schizophrenia and bipolar disorder, respectively). In this review, we will focus on how specific synaptogenic growth factors and their downstream signaling pathways might be involved in the development of neuropsychiatric diseases.
- Published
- 2014
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42. Synapse maturation by activity-dependent ectodomain shedding of SIRPα.
- Author
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Toth AB, Terauchi A, Zhang LY, Johnson-Venkatesh EM, Larsen DJ, Sutton MA, and Umemori H
- Subjects
- Animals, Cells, Cultured, Female, HEK293 Cells, Hippocampus physiology, Hippocampus ultrastructure, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Organ Culture Techniques, Protein Structure, Tertiary physiology, Excitatory Postsynaptic Potentials physiology, Receptors, Immunologic physiology, Synapses physiology, Synapses ultrastructure
- Abstract
Formation of appropriate synaptic connections is critical for proper functioning of the brain. After initial synaptic differentiation, active synapses are stabilized by neural activity-dependent signals to establish functional synaptic connections. However, the molecular mechanisms underlying activity-dependent synapse maturation remain to be elucidated. Here we show that activity-dependent ectodomain shedding of signal regulatory protein-α (SIRPα) mediates presynaptic maturation. Two target-derived molecules, fibroblast growth factor 22 and SIRPα, sequentially organize the glutamatergic presynaptic terminals during the initial synaptic differentiation and synapse maturation stages, respectively, in the mouse hippocampus. SIRPα drives presynaptic maturation in an activity-dependent fashion. Remarkably, neural activity cleaves the extracellular domain of SIRPα, and the shed ectodomain in turn promotes the maturation of the presynaptic terminal. This process involves calcium/calmodulin-dependent protein kinase, matrix metalloproteinases and the presynaptic receptor CD47. Finally, SIRPα-dependent synapse maturation has an impact on synaptic function and plasticity. Thus, ectodomain shedding of SIRPα is an activity-dependent trans-synaptic mechanism for the maturation of functional synapses.
- Published
- 2013
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43. Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice.
- Author
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Lee CH and Umemori H
- Abstract
In the developing hippocampus, fibroblast growth factor (FGF) 22 promotes the formation of excitatory presynaptic terminals. Remarkably, FGF22 knockout (KO) mice show resistance to generalized seizures in adults as assessed by chemical kindling, a model that is widely used to study epileptogenesis (Terauchi et al., 2010). Repeated injections of low dose pentylenetetrazol (PTZ) induce generalized seizures ("kindled") in wild type (WT) mice. With additional PTZ injections, FGF22KO mice do show moderate seizures, but they do not kindle. Thus, analyses of how FGF22 impacts seizure susceptibility will contribute to the better understanding of the molecular and cellular mechanisms of epileptogenesis. To decipher the roles of FGF22 in the seizure phenotype, we examine four pathophysiological changes in the hippocampus associated with epileptogenesis: enhancement of dentate neurogenesis, hilar ectopic dentate granule cells (DGCs), increase in hilar cell death, and formation of mossy fiber sprouting (MFS). Dentate neurogenesis is enhanced, hilar ectopic DGCs appeared, and hilar cell death is increased in PTZ-kindled WT mice relative to PBS-injected WT mice. Even in WT mice with fewer PTZ injections, which showed only mild seizures (so were not kindled), neurogenesis, hilar ectopic DGCs, and hilar cell death are increased, suggesting that mild seizures are enough to induce these changes in WT mice. In contrast, PTZ-injected FGF22KO mice do not show these changes despite having moderate seizures: neurogenesis is rather suppressed, hilar ectopic DGCs do not appear, and hilar cell death is unchanged in PTZ-injected FGF22KO mice relative to PBS-injected FGF22KO mice. These results indicate that FGF22 plays important roles in controlling neurogenesis, ectopic migration of DGCs, and hilar cell death after seizures, which may contribute to the generalized seizure-resistant phenotype of FGF22KO mice and suggests a possibility that inhibition of FGF22 may alleviate epileptogenesis.
- Published
- 2013
- Full Text
- View/download PDF
44. Neurogenesis is enhanced and mossy fiber sprouting arises in FGF7-deficient mice during development.
- Author
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Lee CH, Javed D, Althaus AL, Parent JM, and Umemori H
- Subjects
- Animals, Dentate Gyrus cytology, Dentate Gyrus growth & development, Dentate Gyrus physiology, Mice, Mice, Knockout, Mossy Fibers, Hippocampal ultrastructure, Seizures chemically induced, Seizures genetics, Seizures physiopathology, Synapses physiology, Synapses ultrastructure, Synaptic Potentials, Fibroblast Growth Factor 7 genetics, Mossy Fibers, Hippocampal physiology, Neurogenesis
- Abstract
One of the most common types of epilepsy in adults is temporal lobe epilepsy. Temporal lobe epilepsy is often resistant to pharmacological treatment, requiring urgent understanding of its molecular and cellular mechanisms. It is generally accepted that an imbalance between excitatory and inhibitory inputs is related to epileptogenesis. We have recently identified that fibroblast growth factor (FGF) 7 is critical for inhibitory synapse formation in the developing hippocampus. Remarkably, FGF7 knockout mice are prone to epileptic seizures induced by chemical kindling (Terauchi et al., 2010). Here we show that FGF7 knockout mice exhibit epileptogenesis-related changes in the hippocampus even without kindling induction. FGF7 knockout mice show mossy fiber sprouting and enhanced dentate neurogenesis by 2 months of age, without apparent spontaneous seizures. These results suggest that FGF7-deficiency impairs inhibitory synapse formation, which results in mossy fiber sprouting and enhanced neurogenesis during development, making FGF7 knockout mice vulnerable to epilepsy., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
45. Specific sets of intrinsic and extrinsic factors drive excitatory and inhibitory circuit formation.
- Author
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Terauchi A and Umemori H
- Subjects
- Animals, Brain cytology, Brain physiology, Humans, Nerve Net cytology, Nerve Net physiology, Brain growth & development, Nerve Net growth & development, Neural Inhibition physiology, Synaptic Transmission physiology
- Abstract
How are excitatory (glutamatergic) and inhibitory (GABAergic) synapses established? Do distinct molecular mechanisms direct differentiation of glutamatergic and GABAergic synapses? In the brain, glutamatergic and GABAergic synaptic connections are formed with specific patterns. To establish such precise synaptic patterns, neurons pass through multiple checkpoints during development, such as cell fate determination, cell migration and localization, axonal guidance and target recognition, and synapse formation. Each stage offers key molecules for neurons/synapses to obtain glutamatergic or GABAergic specificity. Some mechanisms are based on intrinsic systems to induce gene expression, whereas others are based on extrinsic systems mediated by cell-cell or axon-target interactions. Recent studies indicate that specific formation of glutamatergic and GABAergic synapses is controlled by the expression or activation of different sets of molecules during development. In this review, the authors outline stages critical to the determination of glutamatergic or GABAergic specificity and describe molecules that act as determinants of specificities in each stage, with a particular focus on the synapse formation stage. They also discuss possible mechanisms underlying glutamatergic and GABAergic synapse formation via synapse-type specific synaptic organizers.
- Published
- 2012
- Full Text
- View/download PDF
46. Fibroblast growth factor 22 contributes to the development of retinal nerve terminals in the dorsal lateral geniculate nucleus.
- Author
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Singh R, Su J, Brooks J, Terauchi A, Umemori H, and Fox MA
- Abstract
At least three forms of signaling between pre- and postsynaptic partners are necessary during synapse formation. First, "targeting" signals instruct presynaptic axons to recognize and adhere to the correct portion of a postsynaptic target cell. Second, trans-synaptic "organizing" signals induce differentiation in their synaptic partner so that each side of the synapse is specialized for synaptic transmission. Finally, in many regions of the nervous system an excess of synapses are initially formed, therefore "refinement" signals must either stabilize or destabilize the synapse to reinforce or eliminate connections, respectively. Because of both their importance in processing visual information and their accessibility, retinogeniculate synapses have served as a model for studying synaptic development. Molecular signals that drive retinogeniculate "targeting" and "refinement" have been identified, however, little is known about what "organizing" cues are necessary for the differentiation of retinal axons into presynaptic terminals. To identify such "organizing" cues, we used microarray analysis to assess whether any target-derived "synaptic organizers" were enriched in the mouse dorsal lateral geniculate nucleus (dLGN) during retinogeniculate synapse formation. One candidate "organizing" molecule enriched in perinatal dLGN was FGF22, a secreted cue that induces the formation of excitatory nerve terminals in muscle, hippocampus, and cerebellum. In FGF22 knockout mice, the development of retinal terminals in dLGN was impaired. Thus, FGF22 is an important "organizing" cue for the timely development of retinogeniculate synapses.
- Published
- 2012
- Full Text
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47. Multiple forms of activity-dependent competition refine hippocampal circuits in vivo.
- Author
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Yasuda M, Johnson-Venkatesh EM, Zhang H, Parent JM, Sutton MA, and Umemori H
- Subjects
- Animals, Axons physiology, Cellular Senescence physiology, Dentate Gyrus cytology, Dentate Gyrus physiology, Entorhinal Cortex cytology, Entorhinal Cortex physiology, Gene Silencing, Hippocampus physiology, Mice, Mice, Transgenic, Neural Pathways cytology, Neural Pathways physiology, Neurogenesis physiology, Neuronal Plasticity, Neurons cytology, Hippocampus cytology, Memory physiology, Neural Inhibition physiology, Neural Pathways growth & development, Neurons physiology
- Abstract
Efficient memory formation relies on the establishment of functional hippocampal circuits. It has been proposed that synaptic connections are refined by neural activity to form functional brain circuitry. However, it is not known whether and how hippocampal connections are refined by neural activity in vivo. Using a mouse genetic system in which restricted populations of neurons in the hippocampal circuit are inactivated, we show that inactive axons are eliminated after they develop through a competition with active axons. Remarkably, in the dentate gyrus, which undergoes neurogenesis throughout life, axon refinement is achieved by a competition between mature and young neurons. These results demonstrate that activity-dependent competition plays multiple roles in the establishment of functional memory circuits in vivo., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
48. Secreted factors as synaptic organizers.
- Author
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Johnson-Venkatesh EM and Umemori H
- Subjects
- Animals, Cell Differentiation, Humans, Nerve Growth Factors metabolism, Neuromuscular Junction metabolism, Neurons cytology, Synapses metabolism, Synapses ultrastructure
- Abstract
A critical step in synaptic development is the differentiation of presynaptic and postsynaptic compartments. This complex process is regulated by a variety of secreted factors that serve as synaptic organizers. Specifically, fibroblast growth factors, Wnts, neurotrophic factors and various other intercellular signaling molecules are proposed to regulate presynaptic and/or postsynaptic differentiation. Many of these factors appear to function at both the neuromuscular junction and in the central nervous system, although the specific function of the molecules differs between the two. Here we review secreted molecules that organize the synaptic compartments and discuss how these molecules shape synaptic development, focusing on mammalian in vivo systems. Their critical role in shaping a functional neural circuit is underscored by their possible link to a wide range of neurological and psychiatric disorders both in animal models and by mutations identified in human patients., (© The Authors (2010). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)
- Published
- 2010
- Full Text
- View/download PDF
49. Distinct FGFs promote differentiation of excitatory and inhibitory synapses.
- Author
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Terauchi A, Johnson-Venkatesh EM, Toth AB, Javed D, Sutton MA, and Umemori H
- Subjects
- Animals, Cells, Cultured, Dendrites metabolism, Disease Susceptibility, Epilepsy chemically induced, Epilepsy genetics, Epilepsy physiopathology, Fibroblast Growth Factor 7 deficiency, Fibroblast Growth Factor 7 genetics, Fibroblast Growth Factors deficiency, Fibroblast Growth Factors genetics, Gene Expression Profiling, Glutamic Acid metabolism, Hippocampus cytology, Hippocampus embryology, Hippocampus metabolism, Hippocampus pathology, In Situ Hybridization, Kindling, Neurologic, Mice, Mice, Knockout, Miniature Postsynaptic Potentials physiology, Presynaptic Terminals classification, Presynaptic Terminals metabolism, Presynaptic Terminals pathology, Presynaptic Terminals ultrastructure, Pyramidal Cells cytology, Pyramidal Cells metabolism, Pyramidal Cells pathology, Receptors, Fibroblast Growth Factor metabolism, Seizures chemically induced, Seizures genetics, Seizures radiotherapy, Synapses pathology, Synapses ultrastructure, Synaptic Transmission, Synaptic Vesicles metabolism, Synaptic Vesicles pathology, Synaptic Vesicles ultrastructure, gamma-Aminobutyric Acid metabolism, Cell Differentiation, Excitatory Postsynaptic Potentials physiology, Fibroblast Growth Factor 7 metabolism, Fibroblast Growth Factors metabolism, Inhibitory Postsynaptic Potentials physiology, Synapses classification, Synapses metabolism
- Abstract
The differential formation of excitatory (glutamate-mediated) and inhibitory (GABA-mediated) synapses is a critical step for the proper functioning of the brain. An imbalance in these synapses may lead to various neurological disorders such as autism, schizophrenia, Tourette's syndrome and epilepsy. Synapses are formed through communication between the appropriate synaptic partners. However, the molecular mechanisms that mediate the formation of specific synaptic types are not known. Here we show that two members of the fibroblast growth factor (FGF) family, FGF22 and FGF7, promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers. FGF22 and FGF7 are expressed by CA3 pyramidal neurons in the hippocampus. The differentiation of excitatory or inhibitory nerve terminals on dendrites of CA3 pyramidal neurons is specifically impaired in mutants lacking FGF22 or FGF7. These presynaptic defects are rescued by postsynaptic expression of the appropriate FGF. FGF22-deficient mice are resistant to epileptic seizures, and FGF7-deficient mice are prone to them, as expected from the alterations in excitatory/inhibitory balance. Differential effects of FGF22 and FGF7 involve both their distinct synaptic localizations and their use of different signalling pathways. These results demonstrate that specific FGFs act as target-derived presynaptic organizers and help to organize specific presynaptic terminals in the mammalian brain.
- Published
- 2010
- Full Text
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50. Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour.
- Author
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Taniguchi S, Nakazawa T, Tanimura A, Kiyama Y, Tezuka T, Watabe AM, Katayama N, Yokoyama K, Inoue T, Izumi-Nakaseko H, Kakuta S, Sudo K, Iwakura Y, Umemori H, Inoue T, Murphy NP, Hashimoto K, Kano M, Manabe T, and Yamamoto T
- Subjects
- Animals, Cell Line, Depression genetics, Depression psychology, Disease Models, Animal, Down-Regulation genetics, Gene Knock-In Techniques, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenylalanine genetics, Phosphorylation genetics, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Receptors, N-Methyl-D-Aspartate genetics, Receptors, N-Methyl-D-Aspartate metabolism, Signal Transduction genetics, Tyrosine genetics, Depression metabolism, Depression physiopathology, Receptors, N-Methyl-D-Aspartate physiology, Tyrosine physiology
- Abstract
Major depressive and bipolar disorders are serious illnesses that affect millions of people. Growing evidence implicates glutamate signalling in depression, though the molecular mechanism by which glutamate signalling regulates depression-related behaviour remains unknown. In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to depression-related behaviour. The NR2A subunit of the NMDA receptor is tyrosine-phosphorylated, with Tyr 1325 as its one of the major phosphorylation site. We have generated mice expressing mutant NR2A with a Tyr-1325-Phe mutation to prevent the phosphorylation of this site in vivo. The homozygous knock-in mice show antidepressant-like behaviour in the tail suspension test and in the forced swim test. In the striatum of the knock-in mice, DARPP-32 phosphorylation at Thr 34, which is important for the regulation of depression-related behaviour, is increased. We also show that the Tyr 1325 phosphorylation site is required for Src-induced potentiation of the NMDA receptor channel in the striatum. These data argue that Tyr 1325 phosphorylation regulates NMDA receptor channel properties and the NMDA receptor-mediated downstream signalling to modulate depression-related behaviour.
- Published
- 2009
- Full Text
- View/download PDF
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