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. 2012 Sep;71(9):814-25.
doi: 10.1097/NEN.0b013e318267b5af.

Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy

Kjell Heuser  1 , Tore Eid, Fredrik Lauritzen, Anna E Thoren, Gry F Vindedal, Erik Taubøll, Leif Gjerstad, Dennis D Spencer, Ole P Ottersen, Erlend A Nagelhus, Nihal C de Lanerolle
Affiliations

Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy

Kjell Heuser et al. J Neuropathol Exp Neurol. 2012 Sep.

Abstract

Recent experimental data in mice have shown that the inwardly rectifying K channel Kir4.1 mediates K spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.1 in hippocampi from patients with medication-refractory temporal lobe epilepsy. The selectivity of the antibody was confirmed in mice with a glial conditional deletion of the gene encoding Kir4.1. These mice showed a complete loss of labeled cells, indicating that Kir4.1 is restricted to glia. In human cases, Kir4.1 immunoreactivity observed in cells morphologically consistent with astrocytes was significantly reduced in 12 patients with hippocampal sclerosis versus 11 patients without sclerosis and 4 normal autopsy controls. Loss of astrocytic Kir4.1 immunoreactivity was most pronounced around vessels and was restricted to gliotic areas. Loss of Kir4.1 expression was associated with loss of dystrophin and α-syntrophin, but not with loss of β-dystroglycan, suggesting partial disruption of the dystrophin-associated protein complex. The changes identified in patients with hippocampal sclerosis likely interfere with K homeostasis and may contribute to the epileptogenicity of the sclerotic hippocampus.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of Kir4.1 immunoreactivity in coronal sections of hippocampi from non-epileptic autopsy controls and patients with temporal lobe epilepsy. ( A-L) Kir4.1 labeling in subfields of the hippocampal formation from autopsy controls (A, D, G, J), patients without hippocampal sclerosis (non-MTLE) (B, E, H, K), and patients with hippocampal sclerosis (MTLE) (C, F, I, L). In autopsy controls and non-MTLE cases Kir4.1 immunoreactivity resides in cells with morphology typical of astrocytes, including their somata (arrowheads), processes (double arrowheads in E), and perivascular end-feet (arrows). Hippocampi from patients with MTLE show a substantial loss of astrocytic Kir4.1 immunoreactivity in areas with neuronal loss and gliosis (F, I). Thus, the sclerotic CA1 are almost devoid of Kir4.1 labeling (I). The hilus shows changes that are somewhat less extensive than those in CA1 (F). Loss of perivascular Kir4.1 immunoreactivity is associated with reduced labeling of astrocytes. The subiculum in MTLE (L) displays a labeling pattern similar to that observed in autopsy controls (J) and non-MTLE (K). The sclerotic area in CA1 in MTLE is marked with dashed line (C). Vertical panels (D, G, J), (E, H, K) and (F, I, L) are high-magnification fields of the respective areas in A, B and C. Scale bars: A-C, 1 mm; D-I, 50 µm; J-L, 100 µm.
Figure 2
Figure 2
Distribution of Kir4.1 immunoreactivity in coronal sections of the hippocampus from wild-type and glial-conditional Kir4.1 knockout mice. (A) Distinct Kir4.1 immunoreactivity is seen in astrocytes (arrowheads) throughout the hippocampus in a wild-type mouse. (B) Absence of astrocytic Kir4.1 labeling in glial-conditional Kir4.1 knockout (cKir4.1−/−) mice attests to the selectivity of the anti-Kir4.1 antibody. Only weak nonspecific nuclear labeling remains after conditional Kir4.1 gene deletion. Boxes indicate regions shown by high magnification in insets. Scale bars: 200 µm; inset, 100 µm.
Figure 3
Figure 3
Distribution of dystrophin immunoreactivity in coronal sections of the hippocampus in patients with temporal lobe epilepsy (TLE) patients with hippocampal sclerosis (MTLE) and TLE patients without sclerosis (non-MTLE). (A-H) In non-MTLE cases (A, C, E, G), there is strong perivascular dystrophin immunoreactivity (arrows) in all subfields of the hippocampal formation. Astrocytic somata (arrowheads) and non-end foot processes (double arrowheads) are less intensely labeled. In MTLE hippocampal formations (B, D, F, H), perivascular dystrophin immunoreactivity is markedly reduced in sclerotic regions, particularly in CA1 (F). In these subfields, dystrophin immunoreactivity is diffuse throughout the neuropil without demarcation of vessels and astrocytes. Subfields CA2 (B) and subiculum (Sub) (H) exhibit a staining pattern similar to that of non-MTLE (A, G). The sclerotic area in CA1 in MTLE (B) is marked with dashed line. Scale bars: A, B, 1 mm; C-F, 500 µm; G, H, and inset, 50 µm.
Figure 4
Figure 4
Distribution of α-syntrophin immunoreactivity in coronal sections of the hippocampus in a patient with temporal lobe epilepsy (TLE) with hippocampal sclerosis (MTLE) and a TLE patient without sclerosis (non-MTLE). (A-H) In non-MTLE patients (A, C, E, G), there is distinct perivascular α-syntrophin immunoreactivity (arrows) and somewhat weaker labeling of astrocytic somata (arrowhead) in all subfields of the hippocampal formation. In MTLE patients (B, D, F, H), perivascular α-syntrophin labeling is markedly reduced in sclerotic areas, particularly in CA1 (F), but also in the dentate hilus (D) and in CA3. In these subfields the staining is very weak, without demarcation of vessels or astrocytes. Subfields CA2 (B) and subiculum (Sub) (H) display a similar labeling pattern to that in non-MTLE cases (A, G). The sclerotic area in CA1 in MTLE is marked with a dashed line. Scale bars: A, B, 1 mm; C, D, 500 µm; E-H, 50 µm.
Figure 5
Figure 5
Distribution of β-dystroglycan immunoreactivity in coronal hippocampus sections from representative patients with temporal lobe epilepsy (TLE) with hippocampal sclerosis (MTLE) and TLE patients without sclerosis (non-MTLE). (A-H) In both non-MTLE (A, C, E, G) and MTLE patients (B, D, F, H), there is strong perivascular β-dystroglycan immunoreactivity (arrows) in all subfields of the hippocampal formation. Astrocytic somata show no β-dystroglycan labeling. The labeling pattern is indistinguishable between the 2 categories of patients. Sub = subiculum. Scale bars: A, B, 1 mm; C-H, 200 µm.
Figure 6
Figure 6
Nissl staining and immunohistochemical staining of Kir4.1, dystrophin, and β-dystroglycan in the sclerotic CA1 of a patient with temporal lobe epilepsy and hippocampal sclerosis (MTLE). (A-D) Nissl staining shows loss of pyramidal cells and glial proliferation in CA1, indicating hippocampal sclerosis (A). Box in A indicates region shown with higher magnification in B-D. Dashed lines in B and D mark the border of the sclerotic area. Immunostaining with antibodies against Kir4.1 (B) and dystrophin (C) reveal that the perivascular labeling is markedly reduced in the sclerotic region of CA1, while that of β-dystroglycan (D) is maintained. Scale bars: A, 1 mm; B-D, 500 µm.
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References

    1. Engel J, Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Epilepsia. 2003;44:741–751. - PubMed
    1. Wieser HG. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia. 2004;45:695–714. - PubMed
    1. Bordey A, Sontheimer H. Properties of human glial cells associated with epileptic seizure foci. Epilepsy Res. 1998;32:286–303. - PubMed
    1. Hinterkeuser S, Schroder W, Hager G, et al. Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur J Neurosci. 2000;12:2087–2096. - PubMed
    1. Haj-Yasein NN, Jensen V, Vindedal GF, et al. Evidence that compromised K+ spatial buffering contributes to the epileptogenic effect of mutations in the human Kir4.1 gene (KCNJ10) Glia. 2011;59:1635–1642. - PubMed

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