In stroke and several neurodegenerative diseases, malfunction of glutamate (Glu) transporters causes Glu accumulation and triggers excitotoxicity. Many details on the cascade of events in the neurodegenerative process remain unclear. As molecular components of glutamatergic synapses are assembled in Caenorhabditis elegans and as many fundamental cellular processes are conserved from nematodes to humans, we studied Glu-induced necrosis in C. elegans and probed its genetic requirements. We combined Δglt-3, a Glu transporter-null mutation, with expression of a constitutively active form of the alpha subunit of the G protein Gs. While neither Δglt-3 nor expression of the constitutively active form of the alpha subunit of the G protein Gs is severely toxic to C. elegans head interneurons, their combination induces extensive neurodegeneration. Δglt-3-dependent neurodegeneration acts through Ca2+-permeable Glu receptors of the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, requires calreticulin function, and is modulated by calcineurin and type-9 adenylyl cyclase (AC9). We further show that mammalian AC9 hyperactivates mammalian AMPA-receptors (AMPA-Rs) in a Xenopus oocyte expression system, supporting that the relationship between AMPA-Rs hyperactivation and AC9 might be conserved between nematodes and mammals. AMPA-Rs–AC9 synergism is thus critical for nematode excitotoxicity and could potentially be involved in some forms of mammalian neurodegeneration.