Hydrogen sulfide and polysulfides induce GABA/glutamate/d-serine release, facilitate hippocampal LTP, and regulate behavioral hyperactivity
Hiroki Furuie, Yuka Kimura, Tatsuhiro Akaishi, Misa Yamada, Yoshiki Miyasaka, Akiyoshi Saitoh, Norihiro Shibuya, Akiko Watanabe, Naoki Kusunose, Tomoji Mashimo, Takeo Yoshikawa, Mitsuhiko Yamada, Kazuho Abe, Hideo Kimura
Abstract
Abstract Hydrogen sulfide (H 2 S) and polysulfides (H 2 S n , n ≥ 2) are signaling molecules produced by 3-mercaptopyruvate sulfurtransferase (3MST) that play various physiological roles, including the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory formation, by enhancing N-methyl- d -aspartate (NMDA) receptor activity. However, the presynaptic action of H 2 S/H 2 S n on neurotransmitter release, regulation of LTP induction, and animal behavior are poorly understood. Here, we showed that H 2 S/H 2 S 2 applied to the rat hippocampus by in vivo microdialysis induces the release of GABA, glutamate, and d -serine, a co-agonist of NMDA receptors. Animals with genetically knocked-out 3MST and the target of H 2 S 2 , transient receptor potential ankyrin 1 (TRPA1) channels, revealed that H 2 S/H 2 S 2 , 3MST, and TRPA1 activation play a critical role in LTP induction, and the lack of 3MST causes behavioral hypersensitivity to NMDA receptor antagonism, as in schizophrenia. H 2 S/H 2 S n , 3MST, and TRPA1 channels have therapeutic potential for psychiatric diseases and cognitive deficits.