Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity

• Ischaemic brain injury leads to excitotoxicity and cell death.
• The glutamatergic transmission via synaptic NMDA receptors is neuroprotective.
• Non-synaptic NMDA receptors (composed of GluN2B subunits) are excitotoxic.
• Selective inhibition of non-synaptic NMDARs may be beneficial.
• Oxygen–glucose deprivation mimics ischaemic conditions.

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 GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways.