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The Journal of Neuroscience, March 26, 2008, 28(13):3264-3276; doi:10.1523/JNEUROSCI.4980-07.2008

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Neurobiology of Disease
Loss of Astrocytic Domain Organization in the Epileptic Brain

Nancy Ann Oberheim,^1,2 Guo-Feng Tian,¹ Xiaoning Han,¹ Weiguo Peng,¹ Takahiro Takano,¹ Bruce Ransom,² and Maiken Nedergaard¹

¹Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, and ²Department of Neurology, University of Washington, Seattle, Washington 98195

Correspondence should be addressed to Dr. Maiken Nedergaard, Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical School, 601 Elmwood Avenue, Rochester, NY 14642. Email: nedergaard{at}urmc.rochester.edu

Gliosis is a pathological hallmark of posttraumatic epileptic foci, but little is known about these reactive astrocytes beyond their high glial fibrillary acidic protein (GFAP) expression. Using diolistic labeling, we show that cortical astrocytes lost their nonoverlapping domain organization in three mouse models of epilepsy: posttraumatic injury, genetic susceptibility, and systemic kainate exposure. Neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes. Concurrently, spine density was increased on dendrites of excitatory neurons. Suppression of seizures by the common antiepileptic, valproate, reduced the overlap of astrocytic processes. Astrocytic domain organization was also preserved in APP transgenic mice expressing a mutant variant of human amyloid precursor protein despite a marked upregulation of GFAP. Our data suggest that loss of astrocytic domains was not universally associated with gliosis, but restricted to seizure pathologies. Reorganization of astrocytes may, in concert with dendritic sprouting and new synapse formation, form the structural basis for recurrent excitation in the epileptic brain.

Key words: diolistic labeling; EEG; dendritic sprouting; mice model; fluorescence microscopy; glia

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Received Nov. 7, 2007; revised Jan. 8, 2008; accepted Feb. 11, 2008.

Correspondence should be addressed to Dr. Maiken Nedergaard, Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical School, 601 Elmwood Avenue, Rochester, NY 14642. Email: nedergaard{at}urmc.rochester.edu

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