Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors

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 sug gested 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 extrasynap tic NMDAR activation, as well as NMDA bath applica tion, 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 acti vation is innocuous and induces a sustained ERK acti vation. The functional dichotomy between these two NMDAR pools is tightly controlled by glutamate uptake systems. Finally, we demonstrated that the only clini cally approved NMDAR antagonist, memantine, prefer entially antagonizes extrasynaptic NMDARs. Together, these results suggest that extrasynaptic NMDAR activa tion contributes to excitotoxicity and that a selective targeting of the extrasynaptic NMDARs represents a promising therapeutic strategy for brain injuries.— Léveillé, F., El gaamouch, F., Gouix, E., Lecocq, M., Lobner, D., Nicole, O., Buisson, A. Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J. 22, 4258–4271 (2008)