@article{d17b972e2efb4faa8ee5fdb84da7b533,
title = "Hyaluronan synthesis supports glutamate transporter activity",
abstract = "Hyaluronan is synthesized, secreted, and anchored by hyaluronan synthases (HAS) at the plasma membrane and comprises the backbone of perineuronal nets around neuronal soma and dendrites. However, the molecular targets of hyaluronan to regulate synaptic transmission in the central nervous system have not been fully identified. Here, we report that hyaluronan is a negative regulator of excitatory signals. At excitatory synapses, glutamate is removed by glutamate transporters to turn off the signal and prevent excitotoxicity. Hyaluronan synthesized by HAS supports the activity of glial glutamate transporter 1 (GLT1). GLT1 also retracted from cellular processes of cultured astrocytes after hyaluronidase treatment and hyaluronan synthesis inhibition. A serial knockout study showed that all three HAS subtypes recruit GLT1 to cellular processes. Furthermore, hyaluronidase treatment activated neurons in a dissociated rat hippocampal culture and caused neuronal damage due to excitotoxicity. Our findings reveal that hyaluronan helps to turn off excitatory signals by supporting glutamate clearance. (Figure presented.). Cover Image for this issue: doi: 10.1111/jnc.14516.",
keywords = "excitotoxicity, glutamate transporter, hyaluronan, hyaluronan synthase, perineuronal nets",
author = "Hayashi, {Mariko Kato} and Tomoki Nishioka and Hideo Shimizu and Kanako Takahashi and Wataru Kakegawa and Tetsuri Mikami and Yuri Hirayama and Schuichi Koizumi and Sachiko Yoshida and Michisuke Yuzaki and Markku Tammi and Yuko Sekino and Kozo Kaibuchi and Yukari Shigemoto-Mogami and Masato Yasui and Kaoru Sato",
note = "Funding Information: This work was supported by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Takeda Science Foundation, Keio Gijuku Academic Development Funds, Ichiro Kanehara Foundation, JSPS KAKENHI Grant number 17K07344, and a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan and International University of Health and Welfare. We thank Profs. Katsuya Miyake and John Heuser (International University of Health and Welfare), Drs. Keiko Matsuda, Osamu Nagano, Eiji Sugihara, Yoshinori Yuku-take, Profs. Hideyuki Saya and Kenji Tanaka (Keio University), Prof. Hidetoshi Tozaki-Saitoh, and Dr. Tomohiro Yamashita (Kyushu University) for sharing research recourses; Dr. Zhi Zhou (Keio University) and Dr. Tetsushi Sakuma (Hiroshima University) for technical advice on CRISPR-CAS9, Dr. Michiko Yanagisawa and Prof. Kohichi Tanaka (Tokyo Medical and Dental University) for technical advice on the glutamate uptake assay, and Prof. Yu Yamaguchi (Sanford-Burnham Medical Research Institute) for helpful discussions. The monoclonal antibody against GFP, 12A6, was developed by and obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. The authors declare that they have no competing interests. Funding Information: This work was supported by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Takeda Science Foundation, Keio Gijuku Academic Development Funds, Ichiro Kanehara Foundation, JSPS KAKENHI Grant number 17K07344, and a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan and International University of Health and Welfare. We thank Profs. Katsuya Miyake and John Heuser (International University of Health and Welfare), Drs. Keiko Matsuda, Osamu Nagano, Eiji Sugihara, Yoshinori Yukutake, Profs. Hideyuki Saya and Kenji Tanaka (Keio University), Prof. Hidetoshi Tozaki-Saitoh, and Dr. Tomohiro Yamashita (Kyushu University) for sharing research recourses; Dr. Zhi Zhou (Keio University) and Dr. Tetsushi Sakuma (Hiroshima University) for technical advice on CRISPR-CAS9, Dr. Michiko Yanagisawa and Prof. Kohichi Tanaka (Tokyo Medical and Dental University) for technical advice on the glutamate uptake assay, and Prof. Yu Yamaguchi (Sanford-Burnham Medical Research Institute) for helpful discussions. The monoclonal antibody against GFP, 12A6, was developed by and obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. The authors declare that they have no competing interests. All experiments were conducted in compliance with the ARRIVE guidelines. Publisher Copyright: {\textcopyright} 2019 International Society for Neurochemistry",
year = "2019",
month = aug,
doi = "10.1111/jnc.14791",
language = "English",
volume = "150",
pages = "249--263",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "3",
}