RT Journal Article SR Electronic T1 Storage and Uptake of d-Serine into Astrocytic Synaptic-Like Vesicles Specify Gliotransmission JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 3413 OP 3423 DO 10.1523/JNEUROSCI.3497-12.2013 VO 33 IS 8 A1 Martineau, Magalie A1 Shi, Ting A1 Puyal, Julien A1 Knolhoff, Ann M. A1 Dulong, Jérôme A1 Gasnier, Bruno A1 Klingauf, Jürgen A1 Sweedler, Jonathan V. A1 Jahn, Reinhard A1 Mothet, Jean-Pierre YR 2013 UL http://www.jneurosci.org/content/33/8/3413.abstract AB Glial cells are increasingly recognized as active players that profoundly influence neuronal synaptic transmission by specialized signaling pathways. In particular, astrocytes have been shown recently to release small molecules, such as the amino acids l-glutamate and d-serine as “gliotransmitters,” which directly control the efficacy of adjacent synapses. However, it is still controversial whether gliotransmitters are released from a cytosolic pool or by Ca2+-dependent exocytosis from secretory vesicles, i.e., by a mechanism similar to the release of synaptic vesicles in synapses. Here we report that rat cortical astrocytes contain storage vesicles that display morphological and biochemical features similar to neuronal synaptic vesicles. These vesicles share some, but not all, membrane proteins with synaptic vesicles, including the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) synaptobrevin 2, and contain both l-glutamate and d-serine. Furthermore, they show uptake of l-glutamate and d-serine that is driven by a proton electrochemical gradient. d-Serine uptake is associated with vesicle acidification and is dependent on chloride. Whereas l-serine is not transported, serine racemase, the synthesizing enzyme for d-serine, is anchored to the membrane of the vesicles, allowing local generation of d-serine. Finally, we reveal a previously unexpected mutual vesicular synergy between d-serine and l-glutamate filling in glia vesicles. We conclude that astrocytes contain vesicles capable of storing and releasing d-serine, l-glutamate, and most likely other neuromodulators in an activity-dependent manner.