Bell-shaped D-serine actions on hippocampal long-term depression and spatial memory retrieval.

D-Serine, the endogenous coagonist of N-methyl-D-aspartate receptors (NMDARs), is considered to be an important gliotransmitter, and is essential for the induction of long-term potentiation. However, less is known about the role of D-serine in another form of synaptic plasticity, long-term depression (LTD). In this study, we found that exogenous D-serine regulated LTD in the hippocampal CA1 region in a "bell-shaped" concentration-dependent manner through regulating the function of NMDARs in the same manner, whereas endogenous D-serine was activity-dependently released and, in turn, contributed to the induction of LTD during low-frequency stimulation. Furthermore, impairing glial functions with sodium fluoroacetate (NaFAC) reduced the magnitude of LTD, which could be restored by exogenous D-serine, indicating that endogenous D-serine is mainly glia-derived during LTD induction. More interestingly, similar to the effects on LTD, exogenous D-serine enhanced spatial memory retrieval in the Morris water maze in a bell-shaped dose-dependent manner and rescued the NaFAC-induced impairment of memory retrieval, suggesting links between LTD and spatial memory retrieval. Our study thus provides direct evidence of the bell-shaped D-serine actions on hippocampal LTD and spatial memory retrieval, and underscores the importance of D-serine in synaptic plasticity, learning, and memory.