Widespread and Long-Lasting Alterations in GABAA-Receptor Subtypes After Focal Cortical Infarcts in Rats: Mediation by NMDA-Dependent Processes

Abstract

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.

Expression of GABAA receptor α1 subunit mRNA and protein in rat neocortex following photothrombotic infarction

“…In this study, α 1 subunit mRNA transcript and protein expression did not correspond, possibly due to a translation block and/or a post-translational modification reported by others (NeumannHaefelin et al, 1999). Comparison of the present results of α 1 subunit mRNA and protein expression with those of other studies (Neumann-Haefelin et al, 1998, 1999Redecker et al, 2002) revealed several differences. α 1 mRNA levels were shown to increase threefold ipsilaterally at 7 days following photothrombosis of the primary somatosensory cortex (Neumann-Haefelin et al, 1999), whereas a moderate decrease of corresponding protein was observed (Neumann-Haefelin et al, 1998).…”

“…Although immunohistochemical techniques can demonstrate distinct laminar and regional distributions of GABA A R α 1 protein in intact and injured cortex (Fritschy and Mohler, 1995;Redecker et al, 2002), α 1 protein expression levels in this study were assessed from commingled tissue punches taken from different cortical areas; good correlation has been demonstrated between Western immunoblotting and immunohistochemical techniques applied for the analysis of GABA A R subunit proteins (Harris et al, 1994).…”

“…GABAergic neurons provide inhibitory control in the brain and have an important role in selective neuronal degeneration following ischemia and epilepsy (Mileson et al, 1992;Sperk et al, 2004). Photothrombotic brain infarction results in morphological and physiological changes in multiple perilesional and remote areas of the brain (Neumann-Haefelin et al, 1998, 1999Liu et al, 2002;Redecker et al, 2002;Frahm et al, 2004aFrahm et al, ,b, 2006 and an imbalance of excitatory and inhibitory neurotransmission (Schiene et al, 1996;Qu et al, 1998) that reflect various degrees of acute injury of cortex and its subsequent repair, recovery, and reorganization. In addition to augmentation of endogenous protective mechanisms following different pathophysiological conditions, alterations in the kinetics and pharmacology of GABA A Rs may be associated with the development of spontaneous seizure activity (Coulter, 2001;Treiman, 2001;Nishimura et al, 2005) and may contribute to the process of poststroke epileptogenesis (Kelly et al, 2001;Liu et al, 2002;Kharlamov et al, 2003Kharlamov et al, , 2007Karhunen et al, 2007); however, studies of the basic mechanisms of ischemiainduced epileptogenesis have had limited development (Kelly, 2002(Kelly, , 2007.…”

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

“…However, the severity of the primary insult may correlate not only with the extent of the secondary lesion but may also explain reversibility. 117 Interestingly, Witte and co-workers 135 elegantly described widespread and long-lasting dysregulation of the GABAergig system after focal cortical infarcts in regions with and without delayed exofocal cell death.…”

Transient Widespread Blood—Brain Barrier Alterations after Cerebral Photothrombosis as Revealed by Gadofluorine M-Enhanced Magnetic Resonance Imaging

“…Numerous studies have shown that PT induces periinfarct depolarization closely related to CSD (Dietrich et al, 1994;Jander et al, 2000) and other neurophysiologic alterations in the ipsilateral hemisphere such as increased spontaneous activity of neurons (Schiene et al, 1996). Remote molecular alterations encompass upregulation of proinflammatory cytokines and growth factors (Jander et al, 2000;Kleinschnitz et al, 2004), and rearrangement of neurotransmitter receptors (Redecker et al, 2002). Magnetic resonance imaging studies using the contrast agent gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA) as the conventional in vivo marker for the BBB showed early and long-lasting breakdown of the BBB within the PT lesion (Lee et al, 1996;Schroeter et al, 2001;Kleinschnitz et al, 2003).…”