AMPA receptors (AMPARs) are the principal
glutamate receptors mediating fast excitatory synaptic transmission in neurons. Aberrant extracellular
glutamate has long been recognized as a hallmark phenomenon during neuronal excitotoxicity. Excessive
glutamate triggers massive Ca(2+) influx through
NMDA receptors (NMDARs), which in turn can activate Ca(2+)-dependent
protease,
calpain. In the present study, we found that prolonged
NMDA treatment (100 microM, 10 min) caused a sustained and irreversible suppression of AMPAR-mediated currents in cortical pyramidal neurons, which was largely blocked by selective
calpain inhibitors. Biochemical and immunocytochemical studies demonstrated that in cortical cultures, prolonged
glutamate or
NMDA treatment reduced the level of surface and total GluR1, but not GluR2, subunits in a
calpain-dependent manner. Consistent with the in vitro data, in animals exposed to transient ischaemic insults,
calpain was strongly activated, and the AMPAR current density and GluR1 expression level were substantially reduced. Moreover,
calpain inhibitors blocked the ischaemia-induced depression of AMPAR currents, and the NMDAR-induced,
calpain-mediated depression of
AMPA responses was occluded in ischaemic animals. Taken together, our studies show that overstimulation of NMDARs reduces AMPAR functions in cortical pyramidal neurons through activation of endogenous
calpain, and
calpain mediates the ischaemia-induced synaptic depression. The down-regulation of AMPARs by
calpain provides a negative feedback to dampen neuronal excitability in excitotoxic conditions like ischaemia and
epilepsy.