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The Journal of Neuroscience, October 24, 2007, 27(43):11604-11613; doi:10.1523/JNEUROSCI.0983-07.2007
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Neurobiology of Disease
Kainate Seizures Cause Acute Dendritic Injury and Actin Depolymerization In Vivo
Ling-Hui Zeng, * Lin Xu, * Nicholas R. Rensing, Philip M. Sinatra, Steven M. Rothman, andMichael Wong Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
Correspondence should be addressed to Dr. Michael Wong, Department of Neurology, Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: wong_m{at}wustl.edu
Seizures may cause brain injury via a variety of mechanisms, potentially contributing to cognitive deficits in epilepsy patients. Although seizures induce neuronal death in some situations, they may also have "nonlethal" pathophysiological effects on neuronal structure and function, such as modifying dendritic morphology. Previous studies involving conventional fixed tissue analysis have demonstrated a chronic loss of dendritic spines after seizures in animal models and human tissue. More recently, in vivo time-lapse imaging methods have been used to monitor acute changes in spines directly during seizures, but documented spine loss only under severe conditions. Here, we examined effects of secondary generalized seizures induced by kainate, on dendritic structure of neocortical neurons using multiphoton imaging in live mice in vivo and investigated molecular mechanisms mediating these structural changes. Higher-stage kainate-induced seizures caused dramatic dendritic beading and loss of spines within minutes, in the absence of neuronal death or changes in systemic oxygenation. Although the dendritic beading improved rapidly after the seizures, the spine loss recovered only partially over a 24 h period. Kainate seizures also resulted in activation of the actin-depolymerizing factor, cofilin, and a corresponding decrease in filamentous actin, indicating that depolymerization of actin may mediate the morphological dendritic changes. Finally, an inhibitor of the calcium-dependent phosphatase, calcineurin, antagonized the effects of seizures on cofilin activation and spine morphology. These dramatic in vivo findings demonstrate that seizures produce acute dendritic injury in neocortical neurons via calcineurin-dependent regulation of the actin cytoskeleton, suggesting novel therapeutic targets for preventing seizure-induced brain injury.
Key words: epilepsy; seizure; dendrite; kainic acid; cofilin; calcineurin
Received March 5, 2007; revised Aug. 31, 2007; accepted Sept. 9, 2007.
Correspondence should be addressed to Dr. Michael Wong, Department of Neurology, Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: wong_m{at}wustl.edu
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