Excitotoxicity and autophagy: Lurcher may not be a model of "autophagic cell death"

The role of autophagy in excitotoxic cell death caused by excessive activation of glutamate receptors has been a contentious issue. Lurcher (Lc) mutant mice, in which a mutant glutamate receptor causes continuous ion flow and kills cerebellar Purkinje cells, have been cited as a model of cell death resulting from autophagy, or "autophagic cell death," in vivo. Here, we reinvestigated Lc-mediated cell death in heterologous cells and cultured neurons as well as in Lc mice in vivo. We show that Lc-mediated cell death is likely not caused by autophagy, but rather by necrosis with autophagic features. Constitutive ion flux per se causes reduction of intracellular ATP levels, which activates the autophagic pathways. Therefore, activation of autophagy might have a homeostatic protective role to maintain intracellular ATP in the Lc model of excitotoxicity.