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Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

ABSTRACT: Changes in chloride (Cl-) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl- homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA(A) receptor-mediated postsynaptic events, indicating a perturbed Cl- homeostasis. We assessed possible contributions of changes in expression of the potassium-chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from approximately 30% of CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium-sodium-chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABA(A) reversal potentials and suppressed interictal activity. Changes in Cl- transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.

SUBMITTER: Huberfeld G

PROVIDER: S-EPMC6672644 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

Huberfeld Gilles G Wittner Lucia L Clemenceau Stéphane S Baulac Michel M Kaila Kai K Miles Richard R Rivera Claudio C

The Journal of neuroscience : the official journal of the Society for Neuroscience 20070901 37

Changes in chloride (Cl-) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl- homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA(A) re ...[more]

PMID: 17855601

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Project description:BACKGROUND: Human herpesvirus-6 (HHV-6) is a beta-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)-positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters. METHODS AND FINDINGS: HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive-the first demonstration of an ex vivo HHV-6-infected astrocyte culture isolated from HHV-6-positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression. CONCLUSIONS: Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.

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Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

Publications

Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

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