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 journalArticlepeer-review

    119 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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