title: Astroglial d-serine is the endogenous co-agonist at the presynaptic NMDA receptor in rat entorhinal cortex.
abstract: Presynaptic NMDA receptors facilitate the release of glutamate at excitatory cortical synapses and are involved in regulation of synaptic dynamics and plasticity. At synapses in the entorhinal cortex these receptors are tonically activated and provide a positive feedback modulation of the level of background excitation. NMDA receptor activation requires obligatory occupation of a co-agonist binding site, and in the present investigation we have examined whether this site on the presynaptic receptor is activated by endogenous glycine or d-serine. We used whole-cell patch clamp recordings of spontaneous AMPA receptor-mediated synaptic currents from rat entorhinal cortex neurones in vitro as a monitor of presynaptic glutamate release. Addition of exogenous glycine or d-serine had minimal effects on spontaneous release, suggesting that the co-agonist site was endogenously activated and likely to be saturated in our slices. This was supported by the observation that a co-agonist site antagonist reduced the frequency of spontaneous currents. Depletion of endogenous glycine by enzymatic breakdown with a bacterial glycine oxidase had little effect on glutamate release, whereas d-serine depletion with a yeast d-amino acid oxidase significantly reduced glutamate release, suggesting that d-serine is the endogenous agonist. Finally, the effects of d-serine depletion were mimicked by compromising astroglial cell function, and this was rescued by exogenous d-serine, indicating that astroglial cells are the provider of the d-serine that tonically activates the presynaptic NMDA receptor. We discuss the significance of these observations for the aetiology of epilepsy and possible targeting of the presynaptic NMDA receptor in anticonvulsant therapy.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Lench
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Massey
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, Varese, Italy.
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham B4 7ET, United Kingdom.
authors.forename: Gavin L
authors.initials: GL
authors.lastname: Woodhall
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. Electronic address: r.s.g.jones@bath.ac.uk.
authors.forename: Roland S G
authors.initials: RS
authors.lastname: Jones
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D012694:Serine; D005998:Glycine
keywords: Astroglia; Entorhinal cortex; Glutamate release; Glycine; Presynaptic NMDA receptor; d-Serine