Reduced Efficacy of the KCC2 Cotransporter Promotes Epileptic Oscillations in a Subiculum Network Model.
Reduced Efficacy of the KCC2 Cotransporter Promotes Epileptic Oscillations in a Subiculum Network Model.
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DOI：
10.1523/jneurosci.4228-15.2016
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发表时间：
2016-11-16
期刊：
影响因子：
--
通讯作者：
Gutkin BS
中科院分区：
文献类型：
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作者：
Buchin A;Chizhov A;Huberfeld G;Miles R;Gutkin BS
Pharmacoresistant epilepsy is a chronic neurological condition in which a basal brain hyper excitability results in paroxysmal hyper synchronous neuronal discharges. Human temporal lobe epilepsy has been associated with dysfunction or loss of the potassium-chloride co-transporter KCC2 in a subset of pyramidal cells in the subiculum, a key structure generating epileptic activities. KCC2 regulates intra-neuronal chloride and extracellular potassium levels by extruding both ions. Absence of effective KCC2 may alter dynamics of chloride and potassium levels during repeated activation of GABAergic synapses due to interneuron activity. In turn such GABAergic stress may itself affect Cl- regulation. Such changes in ionic homeostasis may switch GABAergic signaling from inhibitory to excitatory in affected pyramidal cells and also increase neuronal excitability. Possibly they contribute to periodic bursting in pyramidal cells, an essential component in the onset of ictal epileptic events. We tested this hypothesis with a computational model of a subicular network with realistic connectivity. The pyramidal cell model explicitly incorporated the cotransporter KCC2 and its effects on the internal/external chloride and potassium levels. Our network model suggested the loss of KCC2 in a critical number of pyramidal cells increased external potassium and intracellular chloride concentrations leading to seizure-like field potential oscillations. These oscillations included transient discharges leading to ictal-like field events with frequency spectra as in vitro. Restoration of KCC2 function suppressed seizure activity and thus may present a useful therapeutic option. These simulations therefore suggest that a reduced KCC2 cotransporter activity alone may underlie the generation of ictal discharges.
