Differential downregulation of GABA(A) receptor subunits in widespread brain regions in the freeze-lesion model of focal cortical malformations

Abstract

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 α1, α2, α3, α5, and γ2 was observed. Within the cortical malformation, this downregulation was most prominent for subunits α5 and γ2, 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 γ2 and moderate for subunits α1, α2, and α5, whereas subunit α3 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.