Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness
Open accessAbstract
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.
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Astrocytes contribute to synaptic modulation and plasticity associated with the activity of long-range cholinergic and noradrenergic fibers.
“Astrocytes contribute also to synaptic modulation and plasticity associated with the activity of long-range cholinergic and noradrenergic fibers 32, 51-55 (Fig. 2 and discussed below).”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [32]
Acetylcholine released during vigilance activates astrocyte networks and promotes astrocyte-mediated neuronal modulation.
“Acetylcholine, which is released during vigilance state by long-range cholinergic fibers (modulating attention and learning), also activates astrocyte networks and promotes astrocyte-mediated neuronal modulation 32, 52, 53, 55, 65 .”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [32]
Astrocytes participate in hippocampus-dependent memory formation by controlling the availability of D-serine for synaptic NMDAR activation.
“Astrocytes also participate in hippocampus-dependent memory formation by controlling the availability of D-serine for synaptic NMDAR activation 7, 32, 48 (see above).”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [32]
Several other studies have not observed leakage of dnSNARE expression in neurons.
“several other studies have not observed this leakage 32, 33, 89”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [32]
In the CNS, nicotinic acetylcholine receptors are expressed in both neurons and non-neuronal cells.
“In the CNS, the nicotinic acetylcholine receptors (nAChRs) are expressed in both neurons and non-neuronal cells.379,380”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [380]
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References 64 · Cited by 243
- Authors
- Papouin, T., Dunphy, J. M., Tolman, M., Dineley, K. T., & Haydon, P. G.
- Affiliations
- Tufts University (US)
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Haydon, Philip G.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 94
- Issue
- 4
- Pages
- 840-854.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5484087
- OpenAlex
- W2611326560
- Cited by
- 243
- References
- 64
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 24 · 2023: 30 · 2022: 25 · 2021: 41 · 2020: 18 · 2019: 27 · 2018: 30 · 2017: 12
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Philippe Foundation
- Human Frontier Science Program (LT000010/2013)
- NIH/NIMH (MH106208)
- NIH/NINDS (NS037585, AA020183)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- D-serine, astrocytes, hippocampus, alpha7 nicotinic acetylcholine receptor, wakefulness, sleep-wake cycle, gliotransmission, synaptic plasticity, learning performance, schizophrenia, cholinergic hypofunction, NMDA receptor activation
- MeSH terms
- Animals, Astrocytes, Behavior, Animal, Chromatography, High Pressure Liquid, Conditioning, Psychological, Electroencephalography, Electromyography, Fear, Hippocampus, Immunohistochemistry, Learning, Memory, Mice, Transgenic, Neck Muscles, Quinuclidines, Schizophrenia, Serine, Synapses, Thiophenes, Wakefulness, Receptors, N-Methyl-D-Aspartate, Microdialysis, Nicotinic Agonists, Excitatory Postsynaptic Potentials, Mice, Optical Imaging, Optogenetics, alpha7 Nicotinic Acetylcholine Receptor
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