Reactive Sulfur Species Emerge as Gliotransmitters to Support Memory via Sulfuration-Dependent Gating of NR2A-Containing N-Methyl-d-Aspartate Subtype Glutamate Receptor Function.

Abstract

Astrocytes have been revealed as a controller of synaptic plasticity and memory via releasing gliotransmitters. Our recent findings showed that reactive sulfur species (RSS), including hydrogen sulfide (H2S) and polysulfide (H2Sn), regulated the availability of d-serine, which is a well-known gliotransmitter that is involved in synaptic plasticity. An interesting question is whether RSS, which are small molecules, can function as direct gliotransmitters to integrate astrocyte-neuron interactions throughout the memory process. We found that hippocampal RSS level increased significantly in response to learning. We further demonstrated that the activity-triggered RSS signal controlled memory formation by using pharmacological and genetic approaches. The RSS-supporting memory was primarily conferred by enzymes that were mainly located in astrocytes, including cystathionine β-synthase (CBS) and mercaptopyruvate sulfurtransferase (3-MST), and the memory-promoting effects were mostly dependent on sulfration of the NR2A subunit of N-methyl-d-aspartate subtype glutamate receptors (NMDARs). Further, RSS were demonstrated to buffer the strong inhibitory effect of synaptically released zinc on NR2A-containing NMDARs. Innovation and Conclusion: These results suggest that glial-derived RSS signals can serve as direct gliotransmitters that regulate memory formation through the redox modulation of postsynaptic receptors; this conclusion will enrich the gliotransmission hypothesis.