Hydrogen sulfide and polysulfides induce GABA/glutamate/D-serine release, facilitate hippocampal LTP, and regulate behavioral hyperactivity.

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.
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