Nutrient Deprivation Enhances Neuronal Survival and Induces Secretion of Protective Extracellular Vesicles

Neurons respond to nutrient deprivation by activating autophagic pathways that promote survival under subsequent metabolic stress. Here, we show that short-term nutrient deprivation or pharmacological inhibition of mTORC1 enhances neuronal resistance to glutamate-induced excitotoxicity in primary cerebellar cultures characterized by a rapid decline in p62/SQSTM1 levels and a decrease in procaspase-3 levels, suggesting a potential mechanism for enhanced cell survival. Importantly, extracellular vesicles (EVs) secreted by the neurons during transient nutrient deprivation protect naïve recipient neurons by activating Akt and reducing excitotoxic cell death, indicating that these vesicles transmit pro-survival signals. Our findings uncover a stress-induced intercellular communication mechanism with therapeutic potential in neuroprotection, ischemic preconditioning, and vesicle-based interventions.