Essential role of PIKE GTPases in neuronal protection against excitotoxic insults

Abstract

Phosphoinositide 3-kinase enhancer (PIKE) is a group of novel GTPases that regulate the PI3K/Akt activity through direct interactions. Previous in vitro studies suggest that PIKE are involved in numerous mechanisms to prevent apoptosis in neurons but their roles in intact animal remain unexplored. Here, we show that neurons with PIKE ablation (PIKE −/−) are hypersensitive to neuroexcitotoxic stimulation as higher Ca2+ permeability and cell death are detected in kainic acid (KA)-treated PIKE −/− neurons. We further examined the neuroprotective role of PIKE in vivo by administrating KA into the knockout animals via intraperitoneal injection. Immunohistological and biochemical analysis reveal that KA injection causes severer neuronal damage in PIKE> −/− brains. The discharge frequency of electroencephalogram is also higher in PIKE −/− mice after KA administration, results in a stronger epileptogenic behavior in the mutant line. Therefore, our data provide compelling evidence on the neuroprotective role of PIKE GTPases in animals that PIKE proteins are essential for protecting against neurotoxic insults.