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The Journal of Neuroscience, July 1, 2000, 20(13):5045-5053

Differential Downregulation of GABA_A Receptor Subunits in Widespread Brain Regions in the Freeze-Lesion Model of Focal Cortical Malformations

Christoph Redecker¹, Heiko J. Luhmann², Georg Hagemann¹, Jean-Marc Fritschy³, and Otto W. Witte¹

¹ Department of Neurology and ² Institute of Neurophysiology, Heinrich-Heine-University, D-40225 Düsseldorf, Germany, and ³ Institute of Pharmacology, University of Zürich, CH-8057 Zürich, Switzerland

Focal cortical malformations comprise a heterogeneous group of disturbances of brain development, commonly associated with drug-resistant epilepsy and/or neuropsychological deficits. Electrophysiological studies on rodent models of cortical malformations demonstrated intrinsic hyperexcitability in the lesion and the structurally intact surround, indicating widespread imbalances of excitation and inhibition. Here, alterations in regional expression of GABA_A receptor subunits were investigated immunohistochemically in adult rats with focal cortical malformations attributable to neonatal freeze-lesions. These lesions are morphologically characterized by a three- to four-layered cortex with microsulcus formation. Widespread regionally differential reduction of GABA_A receptor subunits 1, 2, 3, 5, and 2 was observed. Within the cortical malformation, this downregulation was most prominent for subunits 5 and 2, whereas medial to the lesion, a significant and even stronger decrease of all subunits was detected. Lateral to the dysplastic cortex, the decrease was most prominent for subunit 2 and moderate for subunits 1, 2, and 5, whereas subunit 3 was not consistently altered. Interestingly, the downregulation of GABA_A receptor subunits also involved the ipsilateral hippocampal formation, as well as restricted contralateral neocortical areas, indicating widespread disturbances in the neocortical and hippocampal network. The described pattern of downregulation of GABA_A receptor subunits allows the conclusion that there is a considerable modulation of subunit composition. Because alterations in subunit composition critically influence the electrophysiological and pharmacological properties of GABA_A receptors, these alterations might contribute to the widespread hyperexcitability and help to explain pharmacotherapeutic characteristics in epileptic patients.

Key words: cortical dysplasia; GABA; epilepsy; hyperexcitability; receptors; immunohistochemistry; developmental lesion

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20135045-09$05.00/0

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