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Long-term potentiation depends on release of d-serine from astrocytes
Open accessAbstract
Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory. The classical form of LTP relies on N-methyl-D-aspartate receptors (NMDARs), and it has been shown that astroglia can regulate their activation through Ca(2+)-dependent release of the NMDAR co-agonist D-serine. Release of D-serine from glia enables LTP in cultures and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus. However, increases in Ca(2+) concentration in astroglia can also release other signalling molecules, most prominently glutamate, ATP and tumour necrosis factor-alpha, whereas neurons themselves can synthesize and supply D-serine. Furthermore, loading an astrocyte with exogenous Ca(2+) buffers does not suppress LTP in hippocampal area CA1 (refs 14-16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca(2+) in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous D-serine or glycine, whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca(2+)-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.
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“The intermediate behavior of astrocytes is therefore consistent with the emerging view that they are not simply support cells, but they play an active role in computational processing (Henneberger et al., 2010).”
From Molecular Architecture of the Mouse Nervous System (2018) · cites this paper as Henneberger et al., 2010
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“classical NMDAR-dependent LTP at hippocampal CA1 synapses requires transient D-serine release from the astrocytes 18, 29, 30 .”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [29]
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“second, a microscale, on the order of a single astrocyte, at which the entire cell activates and may exert a coordinated influence on synaptic ensembles residing in its territory 29, 129”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [29]
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Metadata
- Authors
- Henneberger, C., Papouin, T., Oliet, S. H. R., & Rusakov, D. A.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- Université de Bordeaux (FR)
- Corresponding author
- Oliet, Stéphane H. R.
- Rusakov, Dmitri A.
- Venue
- Nature
- Published
- 2010-01-14
- Volume
- 463
- Issue
- 7278
- Pages
- 232-236
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2807667
- OpenAlex
- W2109909801
- Cited by
- 1,389
- References
- 39
- Citations by year
- 2026: 52 · 2025: 71 · 2024: 63 · 2023: 73 · 2022: 80 · 2021: 122 · 2020: 73 · 2019: 78 · 2018: 91 · 2017: 81 · 2016: 94 · 2015: 78 · 2014: 99 · 2013: 82 · 2012: 103
- FWCI
- 42.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (084311, 91064)
- 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 › Memory and Neural Mechanisms
- Keywords
- long-term potentiation, astrocytes, D-serine, NMDA receptor co-agonist, synaptic plasticity, hippocampal CA1, excitatory synapses, glycine, astrocyte-neuron interaction, memory mechanisms, calcium buffering, glutamate release
- MeSH terms
- Animals, Astrocytes, Calcium, Exocytosis, Glycine, Hippocampus, Male, Memory, Serine, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Rats, Wistar, Long-Term Potentiation, Rats
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