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¹ Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA

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 Ca²⁺ influx through NMDA receptors (NMDARs), which in turn can activate Ca²⁺-dependent protease, calpain. In the present study, we found that prolonged NMDA treatment (100 µM, 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.

(Received 12 October 2006; accepted after revision 17 January 2007; first published online 18 January 2007)
Corresponding author Z. Yan: Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214, USA. Email: zhenyan{at}buffalo.edu

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