Bell-Shaped D-Serine Actions on Hippocampal Long-Term Depression and Spatial Memory Retrieval

• Published in: Cerebral cortex (New York, N.Y. 1991) Vol. 18; no. 10; pp. 2391 - 2401
• Main Authors: Zhang, Zhi, Gong, Neng, Wang, Wei, Xu, Lin, Xu, Tian-Le
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2008; Oxford Publishing Limited (England)
• Subjects: Animals; Astrocytes - metabolism; D-serine; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; glia; hippocampus; Hippocampus - drug effects; Hippocampus - physiology; long-term depression; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - physiology; Male; Memory - drug effects; Memory - physiology; memory retrieval; NMDA receptor; Organ Culture Techniques; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - physiology; Serine - metabolism; Serine - pharmacology; Space Perception - drug effects; Space Perception - physiology; serine; hippocampus; NMDA receptor; memory retrieval; glia; long-term depression
• ISSN: 1047-3211; 1460-2199
• DOI: 10.1093/cercor/bhn008

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.