. Glia-Derived D-Serine Controls NMDA Receptor Activity and Synaptic Memory. Cell. 2006 Feb 1;125:775.

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  1. In previous studies, Sol Snyder and colleagues have shown that astrocytes in vitro and in vivo synthesize D-serine, a powerful coagonist of NMDA receptors. Because of the localization of D-serine and its high affinity for the glycine binding site of the NMDA receptor, Snyder and colleagues have argued that in many regions of the brain, D-serine may be the physiologically relevant NMDA coagonist. In this new paper, Oliet and colleagues now provide strong evidence that astrocyte-derived D-serine is in fact a powerful regulator of a physiologically important process in vivo.

    During lactation, the amount of astrocyte ensheathment of synaptic terminals in the hypothalamic suproptic nucleus changes dramatically, and it has been previously suggested that this change in glial coverage might alter synaptic functioning, thereby altering the amount of hormone release. By comparing the amount of NMDA receptor activity in virgin and lactating animals, Oliet and colleagues have found that as a consequence of this altered glial coverage of synaptic terminals, the amount of D-serine in the cleft as well as the amount of NMDA receptor activity dramatically decreases, leading to less NMDA response during lactation.

    These studies are some of the very first to show that astrocytes play a crucial role in controlling a physiologically important process. The results have broad significance for understanding brain function in general, because Kristin Harris and colleagues have found that synaptic coverage by astrocytes is variable depending on the synapse and brain region.

    An important question raised by these studies is what controls the amount of D-serine that astrocytes release. Might calcium waves that propagate through the glial syncytium in vivo trigger this release, for instance? In fact, a new study from the Nedergaard lab has just found that these glial calcium waves, long observed in vitro, also occur normally in vivo (Wang et al., 2006). Lastly, these questions have very interesting potential implications for understanding Alzheimer disease. Could loss of synapse function in Alzheimer disease, for instance, be caused by diminished glial release of D-serine?

    References:

    . Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Nat Neurosci. 2006 Jun;9(6):816-23. PubMed.

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