Widespread and long-lasting alterations in GABA(A)-receptor subtypes after focal cortical infarcts in rats: mediation by NMDA-dependent processes.

Impairment of inhibitory neurotransmission has been reported to occur in widespread, structurally intact brain regions after focal ischemic stroke. These long-lasting alterations contribute to the functional deficit and influence long-term recovery. Inhibitory neurotransmission is primarily mediated by gamma-aminobutyric acid (GABA)A receptors assembled of five subunits that allow a variety of adaptive changes. In this study, the regional distribution of five major GABA(A)-receptor subunits (alpha1, alpha2, alpha3, alpha5, and gamma2) was analyzed immunohistochemically 1, 7, and 30 days after photochemically induced cortical infarcts. When compared with sham-operated controls, a general and regionally differential reduction in immunostaining was found within the cortex, hippocampus, and thalamus of both hemispheres for almost all subunits. Within ipsilateral and contralateral neocortical areas, a specific pattern of changes with a differential decrease of subunits alpha1, alpha2, alpha5, and gamma2 and a significant upregulation of subunit alpha3 was observed in the contralateral cortex homotopic to the infarct. This dysregulation was most prominent at day 7 and still present at day 30. Interestingly, a single application of the noncompetitive N-methyl-D-aspartate-receptor antagonist MK-801 during lesion induction completely blocked these bihemispheric alterations. Cortical spreading depressions induced by topical application of KCl do not change GABA(A)-receptor subunit expression. As alterations in subtype distribution crucially influence inhibitory function, ischemia-induced modifications in GABA(A)-receptor subtype expression may be of relevance for functional recovery after stroke.