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

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Abstract

Synaptic reorganization in the epileptic hippocampus involves altered excitatory and inhibitory transmission besides the rearrangement of dendritic spines, resulting in altered excitability, ion homeostasis, and cell swelling. The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role in determining the polarity of GABAA receptor-mediated chloride currents. In addition, KCC2 also interacts with the actin cytoskeleton which is critical for dendritic spine morphogenesis, and for the maintenance of glutamatergic synapses and cell volume. Using immunocytochemistry, we examined the cellular and subcellular levels of KCC2 in surgically removed hippocampi of temporal lobe epilepsy (TLE) patients and compared them to control human tissue. We also studied the distribution of KCC2 in a pilocarpine mouse model of epilepsy. An overall increase in KCC2-expression was found in epilepsy and confirmed by Western blots. The cellular and subcellular distributions in control mouse and human samples were largely similar; moreover, changes affecting KCC2-expression were also alike in chronic epileptic human and mouse hippocampi. At the subcellular level, we determined the neuronal elements exhibiting enhanced KCC2 expression. In epileptic tissue, staining became more intense in the immunopositive elements detected in control tissue, and profiles with subthreshold expression of KCC2 in control samples became labelled. Positive interneuron somata and dendrites were more numerous in epileptic hippocampi, despite severe interneuron loss. Whether the elevation of KCC2-expression is ultimately a pro- or anticonvulsive change, or both—behaving differently during ictal and interictal states in a context-dependent manner—remains to be established.

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Abbreviations

CA:

Cornu Ammonis

DAB:

3,3‘diamino-benzidine 4 HCl

DG:

Dentate gyrus

EEG:

Electroencephalogram

GABA:

Gamma-aminobutyric acid

GluR1:

Glutamate receptor 1

KCC2:

Potassium-chloride cotransporter-2

PET:

Positron emission tomography

Pilo:

Pilocarpine

SE:

Status epilepticus

Str:

Stratum

SPECT:

Single-photon emission computerized tomography

TLE:

Temporal lobe epilepsy

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Acknowledgments

The authors are grateful to Drs. M. Palkovits, P. Sótonyi and Zs. Borostyánkői (Semmelweis University, Budapest) for providing control human tissue. We thank Mr. Gergő Botond for his helpful suggestions regarding Western blot experiments. The excellent technical assistance of Ms. E. Simon, K. Lengyel, Mr. Gy. Goda is also acknowledged. This study was supported by grants from OTKA 102802 Hungary, and NS030549NIH.

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Authors and Affiliations

  1. Institute of Experimental Medicine, Hungarian Academy of Science, Budapest, Hungary

    Mária R. Karlócai, Lucia Wittner, Kinga Tóth, Zsófia Maglóczky, Zoja Katarova, Gábor Szabó & Tamás F. Freund

  2. Institute of Cognitive Neuroscience and Psychology, Research Institute of Natural Sciences, Hungarian Academy of Science, 1117, Budapest, Hungary

    Lucia Wittner & Kinga Tóth

  3. National Institute of Clinical Neuroscience, Budapest, 1577, Hungary

    Lucia Wittner, György Rásonyi, Loránd Erőss, Sándor Czirják & Péter Halász

  4. Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA, 95616, USA

    John A. Payne

  5. Department of Biosciences, University of Helsinki, 00014, Helsinki, Finland

    Kai Kaila

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  1. Mária R. Karlócai
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  2. Lucia Wittner
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Correspondence to Mária R. Karlócai.

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Karlócai, M.R., Wittner, L., Tóth, K. et al. Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy. Brain Struct Funct 221, 3601–3615 (2016). https://doi.org/10.1007/s00429-015-1122-8

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