Caspase-mediated degradation of AMPA receptor subunits: A mechanism for preventing excitotoxic necrosis and ensuring apoptosis

Activation of ionotropic glutamate receptors of the AMPA and NMDA subtypes likely contributes to neuronal injury and death in various neurodegenerativ e disorders. Excitotoxicity can manifest as either apoptosis or necrosis, b ut the mechanisms that determine the mode of cell death are not known. We n ow report that levels of AMPA receptor subunits GluR-1 and GluR-4 are rapid ly decreased in cultured rat hippocampal neurons undergoing apoptosis in re sponse to withdrawal of trophic support (WTS), whereas levels of NMDA recep tor subunits NR1, NR2A, and NR2B are unchanged. Exposure of isolated synapt osomal membranes to "apoptotic" cytosolic extracts resulted in rapid degrad ation of AMPA receptor subunits. Treatment of cells and synaptosomal membra nes with the caspase inhibitors prevented degradation of AMPA receptor subu nits, demonstrating a requirement for caspases in the process. Calcium resp onses to AMPA receptor activation were reduced after withdrawal of trophic support and enhanced after treatment with caspase inhibitors. Vulnerability of neurons to excitotoxic necrosis was decreased after withdrawal of troph ic support and potentiated by treatment with caspase inhibitors. Our data i ndicate that caspase-mediated degradation of AMPA receptor subunits occurs during early periods of cell stress and may serve to ensure apoptosis by pr eventing excitotoxic necrosis.