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.
Pubmed ID: 28479102 RIS Download
Mesh terms: Animals | Astrocytes | Behavior, Animal | Chromatography, High Pressure Liquid | Conditioning (Psychology) | Electroencephalography | Electromyography | Excitatory Postsynaptic Potentials | Fear | Hippocampus | Immunohistochemistry | Learning | Memory | Mice | Mice, Transgenic | Microdialysis | Neck Muscles | Nicotinic Agonists | Optical Imaging | Optogenetics | Quinuclidines | Receptors, N-Methyl-D-Aspartate | Schizophrenia | Serine | Synapses | Thiophenes | Wakefulness | alpha7 Nicotinic Acetylcholine Receptor
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