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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 14, 2004; DOI: 10.1124/jpet.104.068478

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*Epilepsy


Received for publication March 16, 2004.
Revised April 14, 2004.
Accepted for publication April 14, 2004.

Epileptogenesis causes acute and chronic increases in GABAA receptor endocytosis that contributes to the induction and maintenance of seizures in the hippocampal culture model of acquired epilepsy

Robert E Blair 1, Sompong Sombati 1, David C Lawrence 1, Brendan D McCay 1, Robert J DeLorenzo 1*

1 Virginia Commonwealth University

* Address correspondence to: E-mail: rdeloren{at}hsc.vcu.edu

Abstract

Altered GABAergic inhibitory tone has been observed in association with a number of both acute and chronic models of epilepsy and is believed to be the result, in part, of a decrease in function of the postsynaptic GABAA receptor (GABAAR). This study was carried out to investigate if alterations in receptor internalization contribute to the decrease in GABAAR function observed with epilepsy, utilizing the hippocampal neuronal culture model of low-Mg2+ induced spontaneous recurrent epileptiform discharges (SREDs) (Sombati and DeLorenzo, 1995). Analysis of GABAAR function in "epileptic" cultures showed a 62% reduction in [3H]-flunitrazepam binding to the GABAA {alpha} receptor subunit and a 50% decrease in GABA currents when compared to controls. Confocal microscopy analysis of immunohistochemical staining of GABAAR {beta}2/{beta}3 subunit expression revealed approximately a 30% decrease of membrane staining in hippocampal cultures displaying SREDs immediately after low-Mg2+ treatment and in the chronic "epileptic" state. Low-Mg2+ treated cultures internalized antibody labeled GABAA receptor with an increase in rate of 68% from control. Inhibition of GABAAR endocytosis in "epileptic" cultures resulted in both a recovery to control levels of membrane GABAA {beta}2/{beta}3 immunostaining and a total blockade of SREDs. These results indicate that altered GABAAR endocytosis contributes to the decrease in GABAAR expression and function observed in this in vitro model of epilepsy and plays a role in causing and maintaining SREDs. Understanding the mechanisms underlying altered GABAAR recycling may offer new insights into the pathophysiology of epilepsy and provide novel therapeutic strategies to treat this major neurological condition.


Key words: GABA, GABAA receptor, endocytosis, epilepsy, epileptogenesis, hippocampal


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