Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity

In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non-synaptic G1uN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways. (C) 2014 Elsevier Inc. All rights reserved.