主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Background: Astrocyte has been revealed as a controller of synaptic plasticity via releasing d-serine as gliotransmitter. However, some current studies indicated that d-serine was mainly produced by neurons, which raises concerns about the nature of the gliotransmission underlay memory. Here, we report that glial-derived hydrogen sulfide (H2S) signal gates D-serine availability in response to neuronal activity to mediate sunaptic plasticity and contexual fear memory. Methods: Behavior test,biochemical assay,western blot analysis,immunohistochemistry,S-sulfhydration (biotin-switch) assay and electrophysiological recording.Results: We found that increased neuronal activity triggered H2S generation and protein sulfhydration both in vito and in vivo. Activity-triggered H2S production was essential for N-methyl-D-aspartate subtype glutamate receptor (NMDAR)-dependent long-term potentiation (LTP) and contexual fear memory. The H2S signal to support synaptic plasticity and memory are primarily conferred by cystathionine beta synthase (CBS), which mainly located in astrocyte, while its promoting effects on LTP are largely dependent on gating the availability of d-serine, a primary coagonist for synaptic NMDARs. We found that H2S increased NMDAR function via sulfhydration and disinhibition of serine racemase (SR), a main synthetase of d-serine. In aged rats,the level of H2S and SR sulfhydration reduced significantly. Exogenous supplement of H2S restored the sulfhydration of SR in aged rats, followed by the improvement of age-related deficits in the LTP. Furthermore,boost of H2S signal in vivo by its donor or gas inhaling enhances contexual fear memory via a NR2A-containing NMDAR-depednent manner. Conclusions: Therefore,these results establish that glial-derived RSS signal may play a critical role in the gliotransmission undearlay synaptic plasticity and provide a direct evidence for the biological significance of endogenous sulfhydration signal in memory.