IRCN Deputy Director / Principal Investigator
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo
Developmental Synapse Elimination in the Cerebellum,
Endocannabinoid-Mediated Modulation of Synaptic Transmission
The brain consists of neural circuits in which neurons are connected through numerous synapses. Information is transmitted at synapses from nerve endings to neurons by chemical substances called neurotransmitters. Therefore, studies on synaptic connectivity and function are crucial for the understanding of brain function. We investigate how the efficacy of synaptic transmission is regulated by endogenous cannabinoids (that is, substances in the brain which behave like cannabis) and how this regulation contributes to various brain functions. We also pursue how synaptic connectivity and function become matured during postnatal development. Specifically, we study the phenomenon known as synapse elimination or synapse pruning in which, among redundant immature synapses formed around birth, unnecessary connections are eliminated while functionally important ones are strengthened. We use the climbing fiber to Purkinje cell synapse in the cerebellum as a model to elucidate the mechanisms of developmental synapse elimination.
Postnatal development of synaptic wiring onto Purkinje cell of the cerebellum.
PC Purkinje cell, CF climbing fiber, GrC granule cell, PF parallel fiber, BC basket cell
Uesaka, N., Abe, M., Konno, K., Yamazaki, M., Sakoori, K., Watanabe, T., Kao, T-H., Mikuni, T., Watanabe, M., Sakimura, K. and Kano M. (2018) Retrograde signaling from progranulin to Sort1 counteracts synapse elimination in the developing cerebellum. Neuron 97: 796-805, 2018.
Choo, M., Miyazaki, T., Yamazaki, M., Kawamura, M., Nakazawa, T., Zhang, J., Tanimura, A., Uesaka, N., Watanabe, M., Sakimura, K. and Kano, M. (2017) Retrograde BDNF to TrkB signaling promotes synapse elimination in the developing cerebellum. Nat Commun 8: 195.
Uesaka, N., Uchigashima, M., Mikuni, T., Nakazawa, T., Nakao, H., Hirai, H., Aiba, A., Watanabe, M. and Kano, M. (2014) Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain. Science 344: 1020-1023.
Kano, M., Ohno-Shosaku, T., Hashimotodani, Y., Uchigashima, M. and Watanabe, M. (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89: 309-380.
Hashimoto, K. and Kano, M. (2003) Functional differentiation of multiple climbing fiber inputs during synapse elimination in the developing cerebellum. Neuron 38: 785-796.
Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A. and Kano, M. (2001) Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31: 463-475.
Ohno-Shosaku, T., Maejima, T. and Kano, M. (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29: 729-738.
Kano, M., Hashimoto, K., Chen, C., Abeliovich, A., Aiba, A., Kurihara, H., Watanabe, M., Inoue, Y. and Tonegawa, S. (1995) Impaired synapse elimination during cerebellar development in PKCγ mutant mice. Cell 83: 1223-1231.
I received a M.D. from Tokyo Medical and Dental University in 1982, and earned a Ph.D. at the University of Tokyo, Graduate School of Medicine in 1986. I became a research associate at Jichi Medical School (Tochigi, Japan). In 1990, I joined the Max-Planck Institute for Biophysical Chemistry (Goettingen, Germany), as a visiting researcher. I returned to Jichi in 1992, and started to examine synapse elimination in the developing cerebellum. I moved to the RIKEN Institute (Wako, Japan) in 1995, and then became a professor of physiology at Kanazawa University, School of Medicine in 1998. In Kanazawa, my group discovered endocannabinoid-mediated retrograde suppression of synaptic transmission. In 2005, I moved to Osaka University, Graduate School of Medicine, and then moved back to the University of Tokyo, Graduate School of Medicine in 2007.