Glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type play an important role in synaptic plasticity and contribute to cell death under excitotoxic conditions. AMPA receptors form heterotetramers of four homologous subunits (GluR1-4), which exist in two functionally different isoforms, flip and flop, generated by alternative splicing. We identified transcripts for alternatively spliced isoforms of AMPA receptor subunits which lack both the flip and the flop exons, in hippocampal and retinal cultures. These transcripts originate AMPA receptor subunits lacking the flip/flop cassette, the fourth transmembrane domain and the intracellular C-terminus. Truncated GluR1 associates with full-length GluR1 and exerts a dominant negative effect, giving rise to non-functional receptors. Moreover, truncated GluR1 reaches the cell surface, but is not efficiently targeted to the synapse. Hippocampal neuronal transfection with truncated GluR1 resulted in a significant reduction in apoptotic neuronal death triggered by toxic concentrations of glutamate. Furthermore, mRNA coding for the truncated subunits is consistently detected in some regions of the brain in epileptic rats and in hippocampal neurons submitted to toxic concentrations of glutamate. The existence of truncated AMPA receptor subunits may constitute an intrinsic neuroprotective mechanism.