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The Journal of Neuroscience, March 5, 2008, 28(10):2527-2538; doi:10.1523/JNEUROSCI.3426-07.2008

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Neurobiology of Disease
Subunit-Specific Trafficking of GABA_A Receptors during Status Epilepticus

Howard P. Goodkin,^1,2 Suchitra Joshi,¹ Zakaria Mtchedlishvili,¹ Jasmit Brar,³ and Jaideep Kapur¹

Departments of ¹Neurology and ²Pediatrics, Health Sciences Center, and ³College of Arts and Sciences, University of Virginia, Charlottesville, Virginia 22908

Correspondence should be addressed to Dr. Howard P. Goodkin, Department of Neurology, University of Virginia, P.O. Box 800394, Charlottesville, VA 22908. Email: hpg9v{at}virginia.edu

It is proposed that a reduced surface expression of GABA_A receptors (GABARs) contributes to the pathogenesis of status epilepticus (SE), a condition characterized by prolonged seizures. This hypothesis was based on the finding that prolonged epileptiform bursting (repetitive bursts of prolonged depolarizations with superimposed action potentials) in cultures of dissociated hippocampal pyramidal neurons (dissociated cultures) results in the increased intracellular accumulation of GABARs. However, it is not known whether this rapid modification in the surface-expressed GABAR pool results from selective, subunit-dependent or nonselective, subunit-independent internalization of GABARs. In hippocampal slices obtained from animals undergoing prolonged SE (SE-treated slices), we found that the surface expression of the GABAR β2/3 and 2 subunits was reduced, whereas that of the subunit was not. Complementary electrophysiological recordings from dentate granule cells in SE-treated slices demonstrated a reduction in GABAR-mediated synaptic inhibition, but not tonic inhibition. A reduction in the surface expression of the 2 subunit, but not the subunit was also observed in dissociated cultures and organotypic hippocampal slice cultures when incubated in an elevated KCl external medium or an elevated KCl external medium supplemented with NMDA, respectively. Additional studies demonstrated that the reduction in the surface expression of the 2 subunit was independent of direct ligand binding of the GABAR. These findings demonstrate that the regulation of surface-expressed GABAR pool during SE is subunit-specific and occurs independent of ligand binding. The differential modulation of the surface expression of GABARs during SE has potential implications for the treatment of this neurological emergency.

Key words: GABA_A receptor; synapse; plasticity; endocytosis; status epilepticus; neuronal excitability

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Received July 27, 2007; revised Jan. 10, 2008; accepted Jan. 30, 2008.

Correspondence should be addressed to Dr. Howard P. Goodkin, Department of Neurology, University of Virginia, P.O. Box 800394, Charlottesville, VA 22908. Email: hpg9v{at}virginia.edu

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