Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Department of Pharmacology, Sanyo-Onoda City University, Sanyo-Onoda, Yamaguchi, Japan.
Sci Rep. 2023 Oct 31;13(1):17663. doi: 10.1038/s41598-023-44877-y.
Hydrogen sulfide (HS) and polysulfides (HS, 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 HS/HS on neurotransmitter release, regulation of LTP induction, and animal behavior are poorly understood. Here, we showed that HS/HS 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 HS, transient receptor potential ankyrin 1 (TRPA1) channels, revealed that HS/HS, 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. HS/HS, 3MST, and TRPA1 channels have therapeutic potential for psychiatric diseases and cognitive deficits.
硫化氢 (HS) 和多硫化物 (HS，n≥2) 是由 3-巯基丙酮酸硫转移酶 (3MST) 产生的信号分子，它们在各种生理过程中发挥作用，包括通过增强 N-甲基-D-天冬氨酸 (NMDA) 受体活性来诱导海马长时程增强 (LTP)，这是记忆形成的突触模型。然而，HS/HS 对神经递质释放、LTP 诱导的调节以及动物行为的突触前作用还知之甚少。在这里，我们表明，通过体内微透析向大鼠海马施加的 HS/HS 诱导 GABA、谷氨酸和 D-丝氨酸的释放，D-丝氨酸是 NMDA 受体的共激动剂。具有基因敲除 3MST 和 HS 靶点瞬时受体电位锚蛋白 1 (TRPA1) 通道的动物表明，HS/HS、3MST 和 TRPA1 激活在 LTP 诱导中起关键作用，而缺乏 3MST 会导致 NMDA 受体拮抗作用的行为敏感性增加，就像精神分裂症一样。HS/HS、3MST 和 TRPA1 通道具有治疗精神疾病和认知障碍的潜力。
