Anesthetic Sevoflurane Causes Rho-Dependent Filopodial Shortening in Mouse NeuronsReportar como inadecuado




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Early postnatal anesthesia causes long-lasting learning and memory impairment in rodents, however, evidence for a specific neurotoxic effect on early synaptogenesis has not been demonstrated. Drebrin A is an actin binding protein whose localization in dendritic protrusions serves an important role in dendritic spine morphogenesis, and is a marker for early synaptogenesis. We therefore set out to investigate whether clinically-relevant concentrations of anesthetic sevoflurane, widely- used in infants and children, alters dendritic morphology in cultured fetal day 16 mouse hippocampal neurons. After 7 days in vitro, mouse hippocampal neurons were exposed to four hours of 3% sevoflurane in 95% air-5% CO2 or control condition 95% air-5% CO2. Neurons were fixed in 4% paraformaldehyde and stained with Alexa Fluor555-Phalloidin, and-or rabbit anti-mouse drebrin A-E antibodies which permitted subcellular localization of filamentous F-actin and-or drebrin immunoreactivity, respectively. Sevoflurane caused acute significant length-shortening in filopodia and thin dendritic spines in days-in-vitro 7 neurons, an effect which was completely rescued by co-incubating neurons with ten micromolar concentrations of the selective Rho kinase inhibitor Y27632. Filopodia and thin spine recovered in length two days after sevoflurane exposure. Yet cluster-type filopodia a precursor to synaptic filopodia were persistently significantly decreased in number on day-in-vitro 9, in part owing to preferential localization of drebrin immunoreactivity to dendritic shafts versus filopodial stalks. These data suggest that sevoflurane induces F-actin depolymerization leading to acute, reversible length-shortening in dendritic protrusions through a mechanism involving in part activation of RhoA-Rho kinase signaling and impairs localization of drebrin A to filopodia required for early excitatory synapse formation.



Autor: Jeffrey H. Zimering, Yuanlin Dong, Fang Fang, Lining Huang, Yiying Zhang, Zhongcong Xie

Fuente: http://plos.srce.hr/



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