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

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 mod els of cortical malformations demonstrated intrinsic hyperexcitability in t he lesion and the structurally intact surround, indicating widespread imbal ances of excitation and inhibition. Here, alterations in regional expressio n of GABA(A) receptor subunits were investigated immunohistochemically in a dult rats with focal cortical malformations attributable to neonatal freeze -lesions. These lesions are morphologically characterized by a three- to fo ur-layered cortex with microsulcus formation. Widespread regionally differe ntial reduction of GABA(A) receptor subunits alpha 1, alpha 2, alpha 3, alp ha 5, and gamma 2 was observed. Within the cortical malformation, this down regulation was most prominent for subunits alpha 5 and gamma 2, whereas med ial to the lesion, a significant and even stronger decrease of all subunits was detected. Lateral to the dysplastic cortex, the decrease was most prom inent for subunit gamma 2 and moderate for subunits alpha 1, alpha 2, and a lpha 5, whereas subunit alpha 3 was not consistently altered. Interestingly , the downregulation of GABA(A) receptor subunits also involved the ipsilat eral hippocampal formation, as well as restricted contralateral neocortical areas, indicating widespread disturbances in the neocortical and hippocamp al network. The described pattern of downregulation of GABA(A) receptor sub units allows the conclusion that there is a considerable modulation of subu nit composition. Because alterations in subunit composition critically infl uence the electrophysiological and pharmacological properties of GABA(A) re ceptors, these alterations might contribute to the widespread hyperexcitabi lity and help to explain pharmacotherapeutic characteristics in epileptic p atients.