Hyaluronan synthesis supports glutamate transporter activity

• Published in: Journal of neurochemistry 2019-08, Vol.150 (3), p.249-263
• Main Authors: Hayashi, Mariko Kato, Nishioka, Tomoki, Shimizu, Hideo, Takahashi, Kanako, Kakegawa, Wataru, Mikami, Tetsuri, Hirayama, Yuri, Koizumi, Schuichi, Yoshida, Sachiko, Yuzaki, Michisuke, Tammi, Markku, Sekino, Yuko, Kaibuchi, Kozo, Shigemoto‐Mogami, Yukari, Yasui, Masato, Sato, Kaoru
• Format: Article
• Language: English
• Subjects: Amino Acid Transport System X-AG - metabolism; Animals; Astrocytes; Astrocytes - metabolism; Brain - metabolism; Cell culture; Central nervous system; Dendrites; Excitotoxicity; glutamate transporter; Glutamic acid transporter; Hippocampus; hyaluronan; hyaluronan synthase; Hyaluronic acid; Hyaluronic Acid - biosynthesis; Mice; Mice, Inbred C57BL; Neurons - metabolism; Perineuronal nets; Rats; Rats, Sprague-Dawley; Synapses; Synaptic transmission; Synaptic Transmission - physiology; Synthesis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14791

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. Cover Image for this issue: doi: 10.1111/jnc.14516. At excitatory synapses, glutamate is removed by glutamate transporters to turn off the signal. Hyaluronan is synthesized, secreted, and anchored by hyaluronan synthases at the plasma membrane. We show that hyaluronan is synthesized to support glutamate uptake by glutamate transporters. Hyaluronan synthases and glutamate transporters form a hyaluronan dependent complex, and are recruited to cellular process tips. These findings reveal that hyaluronan helps to turn off excitatory signals by supporting glutamate clearance for healthy excitatory signal tuning. Cover Image for this issue: doi: 10.1111/jnc.14516.