Functional Consequences of the Disturbances in the GABA-Mediated Inhibition Induced by Injuriesin the Cerebral Cortex

Hindawi Publishing Corporation Neural Plasticity Volume 2011, Article ID 614329, 14 pages doi:10.1155/2011/614329 Review Article Functional Consequences of the Disturbances in the GABA-Mediated Inhibition Induced by Injuries in the Cerebral Cortex Barbara Imbrosci and Thomas Mittmann Institute of Physiology and Pathophysiology, Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany Correspondence should be addressed to Barbara Imbrosci, Received 22 January 2011; Accepted 5 April 2011 Academic Editor: Graziella Di Cristo Copyright © 2011 B. Imbrosci and T. Mittmann. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cortical injuries are often reported to induce a suppression of the intracortical GABAergic inhibition in the surviving, neighbouring neuronal networks. Since GABAergic transmission provides the main source of inhibition in the mammalian brain, this condition may lead to hyperexcitability and epileptiform activity of cortical networks. However, inhibition plays also a crucial role in limiting the plastic properties of neuronal circuits, and as a consequence, interventions aiming to reestablish a normal level of inhibition might constrain the plastic capacity of the cortical tissue. A promising strategy to minimize the deleterious consequences of a modified inhibitory transmission without preventing the potential beneficial effects on cortical plasticity may be to unravel distinct GABAergic signaling pathways separately mediating these positive and negative events. Here, gathering data from several recent studies, we provide new insights to better face with this “double coin” condition in the attempt to optimize the functional recovery of patients. 1. Introduction Cortical injuries are one major cause of death and permanent disabilities worldwide. In the attempt to ameliorate the survival rate and the postlesion rehabilitation of patients, researchers have developed several animal models of cortical injury to reproduce different aspects of this pathological condition. In particular, a great effort has been dedicated in the investigation of the physiological disturbances spreading in the surrounding uninjured tissue and sometimes even in remote brain areas [1]. Even though these lesion-induced functional alterations might notably differ depending on many factors, such as the nature of the insult (cerebrovascular rather than traumatic), the extent of the damage and the cortical structures affected, some pathophysiological events have been systematically reported following many different experimental models of cortical lesion. Interestingly, one of the most frequently observed functional change postlesion is a reduction in the GABAmediated inhibition which, therefore, seems to be (with some degrees of variability) a general phenomenon taking place as a consequence of a massive neuronal death. Because a deficit in the GABAergic transmission might easily compromise the delicate balance between excitatory and inhibitory neurotransmission [2] this lesion-induced phenomenon has been strongly implicated in the generation of hyperexcitable cortical networks [3] and in the genesis of epileptic events often observed after brain injuries [4, 5]. However, the inhibitory action of GABA is going far beyond the control of the excitability of neuronal networks. The temporal and spatial precise release of GABA can also guarantee high specific responses of cortical neurons [6, 7]. Moreover, the GABAergic transmission has a fundamental role in controlling the plastic capacity of cortical networks. On this concern, different studies indicate that if the strength of the GABA-mediated inhibition is falling below a certain 2 threshold, the plastic properties of the cortical networks will be augmented, sometimes even to levels similar to those observed during the critical period for plasticity [8–10]. In light of these findings, the impaired inhibitory transmission observed postlesion might not be only a deleterious process but, by enhancing the plastic capacity of the cortex, could also promote the functional reorganization of the surrounding uninjured cortical tissue contributing to the functional recovery from the lesion-induced neurological deficits. The injury-induced reduction of inhibition may, therefore, share both detrimental and beneficial effects. Unraveling distinct GABAergic signaling pathways separately mediating these positive and negative events could be extremely helpful in the design of a more effective postlesion rehabilitation therapy. In the attempt to provide new insights to better face with this “double coin” condition, in this paper we will discuss several studies which documented a reduced and/or an altered GABAergic transmission as a consequence of a lesion in the cerebral cortex, and most importantly, we will try to explain how and through which cellular mechanisms the altered GABAergic transmission could influence functions, excitability, and plasticity of cortical networks. 2. Physiology of GABAergic Signaling The GABA receptors are divided into 2 classes: GABAA receptors (GABAA Rs) and GABAB receptors (GABAB Rs) (previously GABAC Rs were considered to form a third separated class; however, because of their strong structural and functional similarity to GABAA Rs, they are today classified as a subfamily of GABAA Rs). GABAARs. GABAA Rs belong to the cys-loop superfamily of ligand-gated ion channels and mediate fast synaptic inhibition in the central nervous system (CNS). GABAA Rs are heteropentameric structure composed by distinct types of subunit. In the mammalian brain, the majority of synaptic GABAA Rs are formed by two α, two β and one γ subunit. Although many different α, β, and γ subunits have been identified (α 1–6, β 1–3, γ 1–3), in the CNS defined combinations of subunits are more frequently found (the most abundant combinations are α1, β2, γ2; α2, β3, γ2; α3, β3, γ2) [11]. Importantly, the combination of these subunits can determine the localization and the functional properties of the receptors. To mention a peculiar example, GABAA Rs in which the γ subunit has been replaced with the δ subunit are exclusively found extrasynaptically [12], are activated by low concentrations of GABA and they display a reduced desensitization [13, 14]. Thanks to these properties δ subunit-containing GABAA Rs are ideally suited to mediate tonic inhibition [15]. GABAA Rs are selectively permeable to Cl− and to a less extent to HCO3 − [16]. Neural Plasticity In the mature CNS, the asymmetrical distribution of Cl− across the membrane (the Cl− inside the cells is maintained relatively low in comparison with the Cl− concentration in the extracellular space, mainly through the action of the potassium-chloride cotransporter 2, KCC2) strongly contribute in defining the reverse pot (...truncated)