Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors
The FASEB Journal. 2008-12-01; 22(12): 4258-4271
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1. FASEB J. 2008 Dec;22(12):4258-71. doi: 10.1096/fj.08-107268. Epub 2008 Aug 18.
Neuronal viability is controlled by a functional relation between synaptic and
extrasynaptic NMDA receptors.
Léveillé F(1), El Gaamouch F, Gouix E, Lecocq M, Lobner D, Nicole O, Buisson A.
(1)UMR 6232 Centre National de la Recherche Scientifique-Université de Caen, GIP
CYCERON, Bd Henri Becquerel, BP 5229 14074 Caen, France.
N-methyl-D-aspartate receptors (NMDARs) are critical for synaptic plasticity that
underlies learning and memory. But, they have also been described as a common
source of neuronal damage during stroke and neurodegenerative diseases. Several
studies have suggested that cellular location of NMDARs (synaptic or
extrasynaptic) is a key parameter controlling their effect on neuronal viability.
The aim of the study was to understand the relation between these two pools of
receptors and to determine their implication in both beneficial and/or
deleterious events related to NMDAR activation. We demonstrated that selective
extrasynaptic NMDAR activation, as well as NMDA bath application, does not
activate extracellular signal-regulated kinase (ERK) pathways, but induces
mitochondrial membrane potential breakdown and triggers cell body and dendrite
damages, whereas synaptic NMDAR activation is innocuous and induces a sustained
ERK activation. The functional dichotomy between these two NMDAR pools is tightly
controlled by glutamate uptake systems. Finally, we demonstrated that the only
clinically approved NMDAR antagonist, memantine, preferentially antagonizes
extrasynaptic NMDARs. Together, these results suggest that extrasynaptic NMDAR
activation contributes to excitotoxicity and that a selective targeting of the
extrasynaptic NMDARs represents a promising therapeutic strategy for brain
PMID: 18711223 [Indexed for MEDLINE]