Work

INF2-mediated actin filament reorganization confers intrinsic resilience to neuronal ischemic injury

Year: 2022

Type: article

Abstract: ABSTRACT During early stages of ischemic brain injury, glutamate receptor hyperactivation mediates neuronal death via osmotic cell swelling. Here we show that ischemia and excess NMDA receptor activation – conditions that trigger neuronal swelling -- cause actin filaments to undergo a rapid and extensive reorganization within the somatodendritic compartment. Normally, F-actin is concentrated within dendritic spines, with relatively little F-actin in the dendrite shaft. However, beginning <5 min after incubation of neurons with NMDA, F-actin depolymerizes within dendritic spines and polymerizes into long, stable filament bundles within the dendrite shaft and soma. A similar “actinification” of the somatodendritic compartment occurs after oxygen/glucose deprivation in vitro , and in mouse brain after photothrombotic stroke in vivo . Following transient, sub-lethal NMDA exposure these actin changes spontaneously reverse within 1-2 hours. A combination of Na + , Cl - , water, and Ca 2+ entry are all necessary, but not individually sufficient, for induction of actinification. Spine F-actin depolymerization is also required. Actinification is driven by activation of the F-actin polymerization factor inverted formin-2 (INF2). Silencing of INF2 renders neurons more vulnerable to NMDA-induced membrane leakage and cell death, and formin inhibition markedly increases ischemic infarct severity in vivo . These results show that ischemia-induced actin filament reorganization within the dendritic compartment is an intrinsic pro-survival response that protects neurons from death induced by swelling.

Source: Nature Communications

DOI: 10.1038/s41467-022-33268-y