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

Thomas Papouin, Jaclyn M. Dunphy, Michaela Tolman, Kelly T. Dineley, Philip G. Haydon

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)840-854.e7
JournalNeuron
Volume94
Issue number4
DOIs
StatePublished - May 17 2017

Keywords

  • D-serine
  • EVP-6124
  • NMDAR
  • acetylcholine
  • astrocytes
  • contextual guidance
  • schizophrenia
  • vigilance state
  • wakefulness
  • α7nAChR

ASJC Scopus subject areas

  • Neuroscience(all)

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