Cortical GABAergic excitation contributes to epileptic activities around human glioma

Abstract

Rationale-Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study.Objective-We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities.Results-Postoperative glioma tissue from 69% of patients spontaneously generated interictallike discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride cotransporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas.Conclusions-Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients.

Acute and Chronic Efficacy of Bumetanide in an in vitro Model of Posttraumatic Epileptogenesis

“…Alterations in neuronal chloride transport after hypoxia-ischemia [11], in acute brain trauma [13] and chronically epileptic tissue [22, 37] raise the possibility that accumulation of [Cl − ] i and excitatory GABA signaling in injured neurons contribute to development of post-traumatic seizures and epileptogenesis. The mechanism of intracellular chloride accumulation in traumatized neurons is complex and has been reported to involve GABA A receptor operated Cl − channels [10, 28], volume-sensitive Cl − channels [38], as well as the cation-chloride co-transporters NKCC1 and KCC2 [11–13] which also subserve chloride homeostasis under control conditions [7, 15, 39, 40].…”

“…One possibility is that injured, gliotic areas have altered extracellular and intracellular macromolecular compositions, which may change the balance of intra and extracellular Donnan forces that set [Cl − ] i and the polarity and magnitude of GABA A receptor activity. Studies in acute brain slice preparations from patients with chronic epilepsy have supported the acute efficacy of bumetanide [22], although the role of acute slice injury on network excitability is difficult to separate from chronic changes in [Cl − ] i in the acute brain slice preparation [13]. We tested whether inhibition of the cation-chloride co-transporter NKCC1 would have acute or chronic effects on spontaneous recurrent ictal-like epileptiform discharges in organotypic hippocampal slice cultures, a rapid in vitro model of post-traumatic epileptogenesis [23–25].…”

The K+–Cl− Cotransporter KCC2 and Chloride Homeostasis: Potential Therapeutic Target in Acute Central Nervous System Injury

“…In a chronically injured cortex, impaired Cl − extrusion in layer V pyramidal neurons due to decreased KCC2 expression can result in GABAergic disinhibition and epileptogenesis [99][100][101]. Additionally, Pallud et al [102] demonstrated that down-regulation of KCC2 perturbs Cl − homeostasis, which contributes to cortical GABAergic excitation and consequent epileptic discharges in glioma patients. Kahle and colleagues described that two functional variants in KCC2, R952H and R1049C, are significantly associated with human idiopathic generalized epilepsy, suggesting that genetically encoded impairment of KCC2 function may be a risk factor for the development of human idiopathic generalized epilepsy [103].…”

In Vivo Tumour Mapping Using Electrocorticography Alterations During Awake Brain Surgery: A Pilot Study

“…Cerebral tumours are known to impair electrogenesis (Schomer and da Silva 2011) and induce epileptogenicity even if underlying mechanisms are far from being elucidated (Pallud et al 2013;Pallud et al 2014). This impairment allows the possibility of monitoring EEG changes in order to map and visualize the tumour before surgical removal.…”