Fig. 2

Age-dependent subunit alternations of synaptic and extrasynaptic NMDA receptors and functional consequences. NMDA receptors are mainly located in the post-synaptic membrane inside and outside of the synaptic cleft. Synaptic NMDARs are directly involved in excitatory neurotransmission and synaptic plasticity, while extrasynaptic NMDARs have regulatory roles in these activities. Glutamate concentrations are markedly different between the cleft and extrasynaptic spaces. Glutamate released by astrocytes and microglia (not shown) are likely the main components of extrasynaptic glutamate, together with that spillover from the synaptic cleft. The distribution and topography of NMDARs are subjected to age-dependent alterations. In addition to a developmental switch of increased GluN2A/GluN2B ratio [340, 341], the GluN3 expression also undergoes an age-dependent change, from the initial locations of both synaptic and extrasynaptic sites to extrasynaptic/peri-synaptic site in the mature brain. This developmental change is likely associated with the functional needs of NMDAR regulation at different life stages. For example, high levels of GluN3A in immature brains is neuroprotective; while in the adult brain, the absence of GluN3 in the synaptic site allows synapse maturation and elevated plasticity. In the adult brain, GluN3 remains to exist in the extrasynaptic membrane as an endogenous neuroprotective mechanism against brain damage and neurodegeneration. In the aging/aged or degenerative brain, loss or weakening of this regulatory mechanism due to either increased GluN2B expression or deficiency of GluN3 will lead to enhanced eNMDA activity and Ca²⁺ dysregulation, which aggravate acute and chronic excitotoxicity associated with ischemic stroke and late-onset AD.