Pro-Survival Responses to Neurocellular Stress

PROJECT SUMMARY Neurons, like other cells, respond to stressful stimuli by mounting a series of pro-survival responses. When the stress is sufficiently mild and/or transient, neurons can recover and resume apparently normal cellular and network function. This proposal builds on our recent discovery of “actinification:” a pro-survival reorganization of the neuronal actin cytoskeleton in response to the perturbed osmoregulation that occurs during stroke in vivo and NMDA receptor hyperactivation in vitro in which F-actin rapidly depolymerizes from dendritic spines and assembles into long, extremely stable filaments within the soma and dendrite. Actinification is induced by the convergence of cell swelling and calcium influx that activates inverted formin 2 (INF2). Direct manipulation of the level and activity of INF2 show that it positively regulates the induction of actinification and subsequent resistance to cell death. Our central hypothesis is that INF2- dependent actin reorganization is an essential mechanism that confers a temporary pro-survival advantage to neurons undergoing excitatory stress by protecting the somatodendritic compartment from acute damage while preserving synaptic circuitry. We propose to apply biochemistry and cell biology approaches to a) identify the molecular mechanisms that underlie INF2-dependent actinification; b) to define how actinification confers resistance to cell death and c) to characterize actinification-associated changes in synapse functionality during stress and recovery. These experiments will accelerate a fundamental understanding of pro-survival responses to stress that are specifically relevant to stroke, seizure, and brain trauma, and broadly relevant to Alzheimer’s and other chronic conditions that are exacerbated by excitotoxicity.