The serine shuttle between glia and neurons: implications for neurotransmission and neurodegeneration

Biochem Soc Trans. 2013 Dec;41(6):1546-50. doi: 10.1042/BST20130220.


D-Serine is a physiological co-agonist of NMDARs (N-methyl-D-aspartate receptors) required for neurotransmission, synaptic plasticity and neurotoxicity. There is no consensus, however, on the relative roles of neurons and astrocytes in D-serine signalling. The effects of D-serine had been attributed to its role as a gliotransmitter specifically produced and released by astrocytes. In contrast, recent studies indicate that neurons regulate their own NMDARs by releasing D-serine via plasma membrane transporters and depolarization-sensitive pathways. Only a minority of astrocytes contain authentic D-serine, whereas neuronal D-serine accounts for up to 90% of the total D-serine pool. Neuronal and glial D-serine production requires astrocytic L-serine generated by a 3-phosphoglycerate dehydrogenase-dependent pathway. These findings support a model whereby astrocyte-derived L-serine shuttles to neurons to fuel the synthesis of D-serine by serine racemase. We incorporate these new findings in a revised model of serine dynamics, called the glia-neuron serine shuttle, which highlights the role of glia-neuron cross-talk for optimal NMDAR activity and brain development.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Humans
  • Nerve Degeneration / metabolism*
  • Neuroglia / metabolism*
  • Neurons / metabolism*
  • Serine / metabolism*
  • Synaptic Transmission*


  • Serine