Astrocytes release D-serine by a large vesicle

Neuroscience. 2013 Jun 14;240:243-57. doi: 10.1016/j.neuroscience.2013.02.029. Epub 2013 Feb 26.


Long-term potentiation (LTP) of synaptic transmission in the CA1 region of the hippocampus depends on the activation of N-methyl-D-aspartate receptors (NMDARs), which can be regulated by Ca²⁺-dependent release of D-serine from astrocytes. The detailed mechanism underlying astrocytic d-serine release is still unknown. In hippocampal slices prepared from Sprague-Dawley rats, we found that clamping astrocytic [Ca²⁺] at 100-150 nM or puffing artificial cerebrospinal fluid (ACSF) into the extracellular space (weak mechanical stimulation) enhanced the synaptic activation of NMDARs. The enhancement was blocked by the NMDAR glycine site antagonist 5,7-dichlorokynurenic acid, glycine saturation, and infusion of astrocytes with D-amino acid oxidase and the serine racemase inhibitor L-erythro-3-hydroxyaspartate, suggesting the involvement of astrocytic D-serine release. Intracellular 100-150 nM [Ca²⁺] or puffing ACSF stimulated astrocytes to generate D-serine-containing large vesicles (1-3 μm), exocytotic fusion of which released D-serine. The formation of astrocytic large vesicles involved the intracellular fusion of small vesicles and/or other organelles. Spontaneous fusion of large vesicles occurred occasionally in astrocytes at rest, contributing to baseline D-serine levels, which increased the rising slope of NMDAR post-burst potentiation (PBP) without altering the PBP peak amplitude. Thus, under physiological conditions, astrocytic D-serine release by large vesicles facilitated weak theta-burst (TBS consisting of five bursts), but not strong TBS (TBS consisting of 10 bursts) stimulation-induced LTP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / pharmacology
  • Animals
  • Animals, Newborn
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / pharmacology
  • Astrocytes / cytology*
  • Astrocytes / drug effects
  • Astrocytes / ultrastructure
  • Biophysics
  • Calcium / metabolism
  • Cytoplasmic Vesicles / drug effects
  • Cytoplasmic Vesicles / metabolism*
  • Cytoplasmic Vesicles / ultrastructure
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Excitatory Amino Acid Agents / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Exocytosis / drug effects
  • Exocytosis / physiology*
  • Female
  • Glycine / pharmacology
  • Hippocampus / cytology
  • In Vitro Techniques
  • Male
  • Microscopy, Electron, Transmission
  • Patch-Clamp Techniques
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Serine / metabolism*
  • Valine / analogs & derivatives
  • Valine / pharmacology


  • Excitatory Amino Acid Agents
  • N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate
  • Purinergic P2Y Receptor Antagonists
  • 3-hydroxyaspartic acid
  • Aspartic Acid
  • Serine
  • Adenosine Diphosphate
  • 2-amino-5-phosphopentanoic acid
  • Valine
  • Calcium
  • Glycine