Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness

Neuron. 2017 May 17;94(4):840-854.e7. doi: 10.1016/j.neuron.2017.04.021. Epub 2017 May 4.


The activation of the N-methyl D-aspartate receptor (NMDAR) is controlled by a glutamate-binding site and a distinct, independently regulated, co-agonist-binding site. In most brain regions, the NMDAR co-agonist is the astrocyte-derived gliotransmitter D-serine. We found that D-serine levels oscillate in mouse hippocampus as a function of wakefulness, in vitro and in vivo. This causes a full saturation of the NMDAR co-agonist site in the dark (active) phase that dissipates to sub-saturating levels during the light (sleep) phase, and influences learning performance throughout the day. We demonstrate that hippocampal astrocytes sense the wakefulness-dependent activity of septal cholinergic fibers through the α7-nicotinic acetylcholine receptor (α7nAChR), whose activation drives D-serine release. We conclude that astrocytes tune the gating of synaptic NMDARs to the vigilance state and demonstrate that this is directly relevant to schizophrenia, a disorder characterized by NMDAR and cholinergic hypofunctions. Indeed, bypassing cholinergic activity with a clinically tested α7nAChR agonist successfully enhances NMDAR activation. VIDEO ABSTRACT.

Keywords: D-serine; EVP-6124; NMDAR; acetylcholine; astrocytes; contextual guidance; schizophrenia; vigilance state; wakefulness; α7nAChR.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Behavior, Animal / drug effects
  • Chromatography, High Pressure Liquid
  • Conditioning, Psychological
  • Electroencephalography
  • Electromyography
  • Excitatory Postsynaptic Potentials*
  • Fear
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Immunohistochemistry
  • Learning
  • Memory
  • Mice
  • Mice, Transgenic
  • Microdialysis
  • Neck Muscles
  • Nicotinic Agonists / pharmacology
  • Optical Imaging
  • Optogenetics
  • Quinuclidines / pharmacology
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Schizophrenia / metabolism*
  • Serine
  • Synapses / metabolism*
  • Thiophenes / pharmacology
  • Wakefulness / drug effects
  • Wakefulness / genetics*
  • alpha7 Nicotinic Acetylcholine Receptor / agonists
  • alpha7 Nicotinic Acetylcholine Receptor / genetics*


  • 7-chloro-N-quinuclidin-3-yl-benzo(b)thiophene-2-carboxamide
  • Chrna7 protein, mouse
  • Nicotinic Agonists
  • Quinuclidines
  • Receptors, N-Methyl-D-Aspartate
  • Thiophenes
  • alpha7 Nicotinic Acetylcholine Receptor
  • Serine