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Antioxid Redox Signal. 2017 Sep 1;27(7):398-414. doi: 10.1089/ars.2016.6936. Epub 2017 Feb 10.

Activity-Dependent Sulfhydration Signal Controls N-Methyl-D-Aspartate Subtype Glutamate Receptor-Dependent Synaptic Plasticity via Increasing d-Serine Availability.

Li YL1, Wu PF1,2,3,4, Chen JG1,2,3,4,5, Wang S6, Han QQ1, Li D7, Wang W1, Guan XL1, Li D1, Long LH1,2,3,4, Huang JG7, Wang F1,2,3,4,5.

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1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
2 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (Huazhong University of Science and Technology) , Wuhan, China .
3 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology , Wuhan, China .
4 Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China , Wuhan, China .
5 The Collaborative Innovation Center for Brain Science , Wuhan, China .
6 School of Life Science and Technology, Huazhong University of Science and Technology , Wuhan, China .
7 Department of Pharmaceutics, College of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .



Reactive sulfur species, including hydrogen sulfide (H2S) and its oxydates, have been raised as novel redox signaling molecules. The present study aimed at examining whether endogenous sulfhydration signal is required for long-term potentiation (LTP), a cellular model for memory.


In this study, we found that increased synaptic activity triggered sulfide generation and protein sulfhydration. Activity-triggered sulfide production was essential for N-methyl-D-aspartate subtype glutamate receptor (NMDAR)-dependent LTP via maintaining the availability of d-serine, a primary coagonist for synaptic NMDARs. Genetic knockdown of cystathionine β-synthase, not cystathionine γ-lyase, impaired LTP. H2S increased NMDAR-dependent LTP via sulfhydration and disinhibition of serine racemase (SR), a main synthetase of d-serine. We found that polysulfides also increased NMDAR-dependent LTP and NMDAR activity. In aged rats, the level of H2S and SR sulfhydration decreased significantly. Exogenous supplement of H2S restored the sulfhydration of SR, followed by the improvement of age-related deficits in LTP. Furthermore, boost of H2S signal in vivo improves hippocampus-dependent memory. Innovation and Conclusion: Our results provide a direct evidence for the biological significance of endogenous sulfhydration signal in synaptic plasticity. Exogenous supplement of H2S could be considered as the new therapeutic approach for the treatment of neurocognitive dysfunction after aging. Antioxid. Redox Signal. 27, 398-414.


cystathionine β-synthase; hydrogen sulfide; serine racemase; sulfhydration; synaptic plasticity

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