The Rise and Fall of the d-Serine-Mediated Gliotransmission Hypothesis

Trends Neurosci. 2016 Nov;39(11):712-721. doi: 10.1016/j.tins.2016.09.007. Epub 2016 Oct 11.


d-Serine modulates N-methyl d-aspartate receptors (NMDARs) and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of d-serine synthesis and release remains controversial, with some arguing that it is a gliotransmitter and others defining it as a neuronal cotransmitter. Results from several laboratories using different strategies now show that the biosynthetic enzyme of d-serine, serine racemase (SR), is expressed almost entirely by neurons, with few astrocytes appearing to contain d-serine. Cell-selective suppression of SR expression demonstrates that neuronal, rather than astrocytic d-serine, modulates synaptic plasticity. Here, we propose an alternative conceptualization whereby astrocytes affect d-serine levels by synthesizing l-serine that shuttles to neurons to fuel the neuronal synthesis of d-serine.

Keywords: N-methyl d-aspartate receptor; d-serine; gliotransmission; glycine; serine racemase; synaptic plasticity.

Publication types

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

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Humans
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Serine / metabolism*
  • Synaptic Transmission / physiology


  • Receptors, N-Methyl-D-Aspartate
  • Serine