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

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.