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

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

Research output: Contribution to journalArticle

55 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. Astrocytes release gliotransmitters at synapses, but how this impacts synaptic physiology over time is unclear. Focusing on the gliotransmitter D-serine, Papouin et al. demonstrate that astrocytes tune synaptic properties to the ongoing brain state, a concept they term "contextual guidance.".

Original languageEnglish (US)
JournalNeuron
DOIs
StateAccepted/In press - Jan 17 2017

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Keywords

  • Acetylcholine
  • Astrocytes
  • Contextual guidance
  • D-serine
  • EVP-6124
  • NMDAR
  • Schizophrenia
  • Vigilance state
  • Wakefulness
  • α7nAChR

ASJC Scopus subject areas

  • Neuroscience(all)

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