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Molecular and Cellular Physiology

Staff List

Professor TABUCHI Katsuhiko
Assistant Professor MORI Takuma, FU Yu

Contact

E-mail : seiri2(at)shinshu-u.ac.jp
※ Change (at) to @ when you send an e-mail.
http://www.shinshu-u.ac.jp/faculty/medicine/chair/i-2seiri/index.html

Summary of Activity

Synapses are sites that connect neurons each other to extend networks in the human brains and transmit signals required for cognition and thought in daily activities.  We intend to uncover mechanisms by which brains function, by studying molecules act at synapses.  We also aim to uncover the pathophysiology of neuropsychiatric disorders caused by dysfunctions of these molecules.

Research Projects

Synapses are highly specialized asymmetric intercellular junctions that transduce chemical signals into the electrical responses that operate communications throughout the nervous system, including the processes underlying perception and thought in the human brain. The orchestration of thousands of molecules localized to pre- and postsynaptic terminals regulates the formation, activation and degeneration of synapses. Hence, the impairment of a portion of these molecules disturbs the coordination of this machinery and results in an aberrant mental condition. A growing body of evidence suggests that synapses play a pivotal role in the pathogenic processes of neurological disorders. Nevertheless, the molecular mechanisms behind such disruptions remain elusive.

We intend to uncover molecular mechanisms affecting synapse in neuropsychiatric disorders. We primarily focus on the synaptic cell adhesion molecules called “Neurexins and Neuroligins” which have been causally implicated in psychiatric disorders including autism, schizophrenia and drug addiction. To this end, we utilize lines of mutant mice that we have generated by gene targeting, and analyze their synaptic functions by multidisciplinary approaches including biochemistry, morphology and electrophysiology. We also study their behavior and assess the relevance between the molecular function and human disorders.

Besides this, we are studying the γ-secretase function in neurodegeneration. We found that the mice lacking Nicastrin, an essential component of γ-secretase, in the brain showed neurodegeneration. We are searching the mechanism by which Nicastrin deficiency causes neurodegeneration.

 

Major Publications

1. Budreck EC, Kwon OB, Jung JH, Baudouin S, Thommen A, Kim HS, Fukazawa Y, Harada H, Tabuchi K, Shigemoto R, Scheiffele P, Kim JH. (2013) Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling.
Proc Natl Acad Sci U S A. 110(2)

2. Yoshida T, Shiroshima T, Lee SJ, Yasumura M, Uemura T, Chen X, Iwakura Y, Mishina M (2012) Receptor Accessory Protein organizes neuronal synaptogenesis as a cell adhesion molecule.  J Neurosci , 32(8):2588-2600

3. Lee SJ, Uemura T, Yoshida T, Mishina M (2012) GluR_2 Assembles Four Neurexins into Trans-Synaptic Triad to Trigger Synapse Formation.  J Neurosci , 32(13):4688-4701

4. Etherton MR, Tabuchi K, Sharma M, Ko J, Sudhof TC. (2011) An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. , 30(14):2908-2919

5. Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J. and Sudhof, T. C. (2011) An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 30(14):2908-19.

6. Uemura T, Lee SJ, Yasumura M, Takeuchi T, Yoshida T, Ra M, Taguchi R, Sakimura K, Mishina M (2010) Trans-synaptic interaction of GluRδ2 and neurexin through Cbln1 mediates synapse formation in the cerebellum.  Cell , 141(6):1068-1079

7. Tabuchi, K., Chen, G., Sudhof, T. C. and Shen, J. (2009) Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration. J Neurosci. 29(22):7290-301.

8. Tabuchi, K., Blundell, J., Etherton, M. R., Hammer, R. E., Liu, X., Powell, C. M. and Sudhof, T. C. (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 318(5847):71-6. *Research Article.

9. Shah, S., *Lee, S. F., *Tabuchi, K., *Hao, Y. H., Yu, C., LaPlant, Q., Ball, H., Dann, C. E., 3rd, Sudhof, T. and Yu, G. (2005) Nicastrin functions as a gamma-secretase-substrate receptor.Cell. 122(3):435-47. *These authors contributed equally to this work

10. Tabuchi, K., Biederer, T., Butz, S. and Sudhof, T. C. (2002) CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1, a novel CASK-binding protein. J Neurosci. 22(11):4264-73.

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