RESEARCH ARTICLE The Insulin/IGF Signaling Regulators Cytohesin/GRP-1 and PIP5K/PPK-1 Modulate Susceptibility to Excitotoxicity in

During ischemic stroke, malfunction of excitatory amino acid transporters and reduced synaptic clearance causes accumulation of Glutamate (Glu) and excessive stimulation of postsynaptic neurons, which can lead to their degeneration by excitotoxicity. The balance between cell death-promoting (neurotoxic) and survival-promoting (neuroprotective) signaling cascades determines the fate of neurons exposed to the excitotoxic insult. The evolutionary conserved Insulin/IGF Signaling (IIS) cascade can participate in this balance, as it controls cell stress resistance in nematodes and mammals. Blocking the IIS cascade allows the transcription factor FoxO3/DAF-16 to accumulate in the nucleus and activate a transcriptional program that protects cells from a range of insults. We study the effect of IIS cascade on neurodegeneration in a C. elegans model of excitotoxicity, where a mutation in a central Glu transporter (glt-3) in a sensitizing background causes Glu-Receptor –dependent neuronal necrosis. We expand our studies on the role of the IIS cascade in determining susceptibility to excitotoxic necrosis b