Molecular and Cellular Physiology

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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 Subject

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. Kim, D., Jung, H., Shirai, Y., Kim, H., Kim, J., Lim, D., Mori, T., Lee, H., Park, D., Kim, H. Y., Guo, Q., Pang, B., Qiu, W., Cao, X., Kouyama-Suzuki, E., Uemura, T., Kasem, E., Fu, Y., Kim, S., Tokunaga, A., Yoshizawa, T., Suzuki, T., Sakagami, H., Lee, K. J., Ko, J., Tabuchi, K., and Um, J. W, IQSEC3 deletion impairs fear memory through upregulation of ribosomal S6 kinase 1 signaling in the hippocampus. Biol Psychiatry in press.

2. Mehta, A., Shirai, Y., Kouyama-Suzuki, E., Zhou, M., Yoshizawa, T., Yanagawa, T., Mori, T. and Tabuchi, K. IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex. Cells 10 (10): 2021.

3. Kim, S., Park, D., Kim, J., Kim, D., Kim, H., Mori, T., Jung, H., Lee, D., Hong, S., Jeon, J., Tabuchi, K., Cheong, E., Kim, J., Um, J. W. and Ko, J. Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior. Cell Rep 36 (3): 109417. 2021

4. Badawi, M., Mori, T., Kurihara, T., Yoshizawa, T., Nohara, K., Kouyama-Suzuki, E., Yanagawa, T., Shirai, Y. and Tabuchi, K. Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1. Front Mol Neurosci 14: 2021

5. Lai, E. S. K., Nakayama, H., Miyazaki, T., Nakazawa, T., Tabuchi, K., Hashimoto, K., Watanabe, M. and Kano, M. An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum. Front Neural Circuits 15: 676891. 2021

6. Suzuki, T., Terada, N., Higashiyama, S., Kametani, K., Shirai, Y., Honda, M., Kai, T., Li, W. and Tabuchi, K. Non-microtubule tubulin-based backbone and subordinate components of postsynaptic density lattices. Life Sci Alliance. 4 (7): 2021

7. Yoshida, T., Yamagata, A., Imai, A., Kim, J., Izumi, H., Nakashima, S., Shiroshima, T., Maeda, A., Iwasawa-Okamoto, S., Azechi, K., Osaka, F., Saitoh, T., Maenaka, K., Shimada, T., Fukata, Y., Fukata, M., Matsumoto, J., Nishijo, H., Takao, K., Tanaka, S., Okabe, S., Tabuchi, K., Uemura, T., Mishina, M., Mori, H. and Fukai, S. Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice. Nat Commun 12 (1): 1848. 2021

8. Cao, X., Qiu, W., Pang, B., Zhou, M., Mehta, A., Guo, Q., Shirai, Y., Mori, T. and Tabuchi, K. Inhibition of CASK Expression by Virus-mediated RNA Interference in Medial Prefrontal Cortex Affects Social Behavior in the Adult Mouse. Shinshu Med J, 69 (1): 45-52. 2021

9. Uemura, T., Suzuki, E., Kawase, S., Kurihara, T., Yasumura, M., Yoshida, T., Fukai, S., Yamazaki, M., Fei, P., Abe, M., Watanabe, M., Sakimura, K., Mishina, M. and Tabuchi, K. Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins. bioRxiv: 2020

10. Cao, X., Kouyama-Suzuki, E., Pang, B., Kurihara, T., Mori, T., Yanagawa, T., Shirai, Y. and Tabuchi, K. Inhibition of DNA ligase IV enhances the CRISPR/Cas9-mediated knock-in efficiency in mouse brain neurons. Biochem Biophys Res Commun 533 (3): 449-457. 2020

11. Kurihara, T., Kouyama-Suzuki, E., Satoga, M., Li, X., Badawi, M., Thiha, Baig, D. N., Yanagawa, T., Uemura, T., Mori, T. and Tabuchi, K. DNA repair protein RAD51 enhances the CRISPR/Cas9-mediated knock-in efficiency in brain neurons. Biochem Biophys Res Commun 524 (3): 621-628. 2020

12. Mori, T., Kasem, E. A., Suzuki-Kouyama, E., Cao, X., Li, X., Kurihara, T., Uemura, T., Yanagawa, T. and Tabuchi, K. Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B. Mol Psychiatry 24 (7): 1079-1092. 2019

13. Han, K. A., Ko, J. S., Pramanik, G., Kim, J. Y., Tabuchi, K., Um, J. W. and Ko, J. PTPsigma Drives Excitatory Presynaptic Assembly via Various Extracellular and Intracellular Mechanisms. J Neurosci 38 (30): 6700-6721. 2018

14. Kasem, E., Kurihara, T. and Tabuchi, K. Neurexins and neuropsychiatric disorders. Neurosci Res 127: 53-60. 2018

15. Cao, X. and Tabuchi, K. Functions of synapse adhesion molecules neurexin/neuroligins and neurodevelopmental disorders. Neurosci Res 116: 3-9. 2017

16. Baig, D. N., Yanagawa, T. and Tabuchi, K. Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders. Brain Res Bull 129: 82-90. 2017

17. Uemura, T., Mori, T., Kurihara, T., Kawase, S., Koike, R., Satoga, M., Cao, X., Li, X., Yanagawa, T., Sakurai, T., Shindo, T. and Tabuchi, K. Fluorescent protein tagging of endogenous protein in brain neurons using CRISPR/Cas9-mediated knock-in and in utero electroporation techniques. Sci Rep 6: 35861. 2016

18. Um, J. W., Choii, G., Park, D., Kim, D., Jeon, S., Kang, H., Mori, T., Papadopoulos, T., Yoo, T., Lee, Y., Kim, E., Tabuchi, K. and Ko, J. IQ Motif and SEC7 Domain-containing Protein 3 (IQSEC3) Interacts with Gephyrin to Promote Inhibitory Synapse Formation. J Biol Chem 291 (19): 10119-30. 2016

19. Anderson, G. R., Aoto, J., Tabuchi, K., Foldy, C., Covy, J., Yee, A. X., Wu, D., Lee, S. J., Chen, L., Malenka, R. C. and Sudhof, T. C. beta-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling. Cell 162 (3): 593-606. 2015

20. Aoto, J., Foldy, C., Ilcus, S. M., Tabuchi, K. and Sudhof, T. C. Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses. Nat Neurosci 18 (7): 997-1007. 2015

21. Ko, J. S., Pramanik, G., Um, J. W., Shim, J. S., Lee, D., Kim, K. H., Chung, G. Y., Condomitti, G., Kim, H. M., Kim, H., de Wit, J., Park, K. S., Tabuchi, K. and Ko, J. PTPsigma functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission. Proc Natl Acad Sci U S A 112 (6): 1874-9. 2015

22. Um, J. W., Pramanik, G., Ko, J. S., Song, M. Y., Lee, D., Kim, H., Park, K. S., Sudhof, T. C., Tabuchi, K. and Ko, J. Calsyntenins function as synaptogenic adhesion molecules in concert with neurexins. Cell Rep 6 (6): 1096-109. 2014

23. Isshiki, M., Tanaka, S., Kuriu, T., Tabuchi, K., Takumi, T. and Okabe, S. Enhanced synapse remodelling as a common phenotype in mouse models of autism. Nat Commun 5: 4742. 2014

24. Aoto, J., Martinelli, D. C., Malenka, R. C., Tabuchi, K. and Sudhof, T. C. Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell 154 (1): 75-88. 2013

25. Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J. and Sudhof, T. C. 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. 2011

26. Etherton, M., Foldy, C., Sharma, M., Tabuchi, K., Liu, X., Shamloo, M., Malenka, R. C. and Sudhof, T. C. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc Natl Acad Sci U S A 108 (33): 13764-9. 2011

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

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

29. 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. Nicastrin functions as a gamma-secretase-substrate receptor. Cell 122 (3): 435-47. 2005

30. Tabuchi, K., Biederer, T., Butz, S. and Sudhof, T. C. 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. 2002