Dysregulation of glutamate signalling is important in Alzheimer's disease and other pathologies.
There has been a focus on changes in neuronal glutamate signalling, but microglia also express
glutamate receptors (GluRs), which are known to modulate their responses to neuropathology.
Microglia express both metabotropic and ionotropic GluRs. Among ionotropic GluRs, microglial
AMPA (α-amino-hydroxy-5-methyl-isoxazole-4-propionate)-type of GluRs (AMPA-Rs) are Ca2+ impermeable
due to the expression of subunit GluA2. Upon activation of microglia, expression level of
surface GluA2 subunits significantly increase, while expression of GluA1, A3 and A4 subunits on
membrane surface significantly decrease. Owing to the GluA2 subunits-dominant composition, AMPA-Rs in activated
microglia show little response to Glu. On the other hand, microglia lacking GluA2 show higher Ca2+-permeability, consequently
inducing a significant increase in the release of the pro-inflammatory cytokine, such as TNF-α. It is suggested that
membrane translocation of GluA2-containing AMPA-Rs in activated microglia has functional importance. Thus, dysfunction
or decreased expression of GluA2 reported in patients with neurodegenerative diseases such as Alzheimer’s and
Creutzfeldt-Jakob disease may accelerate Glu neurotoxicity via excess release of proinflammatory cytokines from microglia,
causing more neuronal death.