Positive shifts of the GABAA receptor reversal potential due to altered chloride homeostasis is widespread after status epilepticus

Abstract

SUMMARYPurpose: c-Aminobutyric acid (GABA)ergic transmission plays an important role in the initiation of epileptic activity and the generation of ictal discharges. The functional alterations in the epileptiform hippocampus critically depend on GABAergic mechanisms and cation-chloride cotransporters. Methods: To understand the cellular basis of specific functional alterations in the epileptic hippocampus, we studied physiologic characteristics and pharmacologically isolated evoked GABA A receptor-mediated inhibitory postsynaptic currents (IPSCs) recorded from principal neurons in hippocampal slices from status epilepticus (SE) and control rats using whole-cell and gramicidin perforated patch-clamp recordings. Key Findings: Whereas the resting membrane potential and input resistance were not significantly different between control and epileptic tissue, the reversal potential (E GABA ) of IPSCs was significantly shifted to more positive values in SE rats with regard to the resting membrane potential. Pharmacologic experiments and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) showed that the observed changes in the epileptic tissue were due to a decreased ratio of the main Cl) cotransporter, NKCC1). Significance: Our results suggest that alterations of cation-chloride cotransporter functions, comprising a higher NKCC1 action, contribute to hyperexcitability within the hippocampus following SE.

KCC2 activity is critical in limiting the onset and severity of status epilepticus

“…KCC2 dysfunction is thought to contribute to traumatic brain injury, neuropathic pain, and acute stress (10). Consistent with this, deficits in the activity and expression levels of KCC2 develop rapidly in animal models of SE and persist after its termination (11)(12)(13).…”

“…Consistent with their role in mediating GABAergic inhibition, deficits in the cell surface levels of GABA A Rs and the amplitudes of miniature inhibitory postsynaptic currents are evident in animal models of SE (22)(23)(24). KCC2 deficits are also clear in patients with intractable epilepsy and animal models of seizures (11,13,25). Here we have examined the mechanisms that underlie KCC2 inactivation during neuronal hyperexcitability and whether they contribute to the pathophysiology of SE.…”

“…1A). These results suggested that deficits in KCC2 surface activity could contribute to elevated levels of intracellular Cl -that develop rapidly in animal models of SE and persist after its termination (11)(12)(13).…”

Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy

“…A decrease in KCC2 level occurred in electrically-kindled and pilocarpine-treated mice shortly after the induction of status epilepticus (Barmashenko et al, 2011;Pathak et al, 2007), whereas in the chronic phase KCC2 expression returned to control levels or was even upregulated (Pathak et al, 2007), suggesting that a certain level of reorganization upon seizure activity is necessary for this increase.…”

“…The large variability of the findings regarding KCC2 levels in epileptic tissue is likely due to differences in epilepsy models (Barmashenko et al, 2011;Rivera et al, 2002), phases (acute, latent, chronic (Pathak et al, 2007) and the regions studied e.g. neocortex (Aronica et al, 2007;Bragin et al, 2009;Talos et al, 2012), hippocampus (Munoz et al, 2007), or subiculum (Huberfeld et al, 2007;Munoz et al, 2007).…”