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Glia. 2017 Nov;65(11):1809-1820. doi: 10.1002/glia.23196. Epub 2017 Aug 10.

Subcellular reorganization and altered phosphorylation of the astrocytic gap junction protein connexin43 in human and experimental temporal lobe epilepsy.

Author information

1
Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Germany.
2
Department of Neurology, Children's Hospital, Chongqing Medical University, Chongqing, China.
3
Department of Neuropathology, Medical Faculty, University of Bonn, Bonn, Germany.
4
Department of Neurosurgery, Medical Faculty, University of Bonn, Bonn, Germany.
5
Department of Epileptology, Medical Faculty, University of Bonn, Bonn, Germany.
6
Institute of Neurology, University College London, London, UK.
7
German Center for Degenerative Diseases (DZNE), Bonn, Germany.

Abstract

Dysfunctional astrocytes are increasingly recognized as key players in the development and progression of mesial temporal lobe epilepsy (MTLE). One of the dramatic changes astrocytes undergo in MTLE with hippocampal sclerosis (HS) is loss of gap junction coupling. To further elucidate molecular mechanism(s) underlying this alteration, we assessed expression, cellular localization and phosphorylation status of astrocytic gap junction proteins in human and experimental MTLE-HS. In addition to conventional confocal analysis of immunohistochemical staining we employed expansion microscopy, which allowed visualization of blood-brain-barrier (BBB) associated cellular elements at a sub-µm scale. Western Blot analysis showed that plasma membrane expression of connexin43 (Cx43) and Cx30 were not significantly different in hippocampal specimens with and without sclerosis. However, we observed a pronounced subcellular redistribution of Cx43 toward perivascular endfeet in HS, an effect that was accompanied by increased plaque size. Furthermore, in HS Cx43 was characterized by enhanced C-terminal phosphorylation of sites affecting channel permeability. Prominent albumin immunoreactivity was found in the perivascular space of HS tissue, indicating that BBB damage and consequential albumin extravasation was involved in Cx43 dysregulation. Together, our results suggest that subcellular reorganization and/or abnormal posttranslational processing rather than transcriptional downregulation of astrocytic gap junction proteins account for the loss of coupling reported in human and experimental TLE. The observations of the present study provide new insights into pathological alterations of astrocytes in HS, which may aid in the identification of novel therapeutic targets and development of alternative anti-epileptogenic strategies.

KEYWORDS:

albumin extravasation; astrocyte; astrocytic endfeet; hippocampal sclerosis; temporal lobe epilepsy

PMID:
28795432
DOI:
10.1002/glia.23196
[Indexed for MEDLINE]

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