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

Autor: Christian Steinhäuser, Michel K. Herde, Martin K. Schwarz, Tingsong Li, Peter Bedner, Tushar Deshpande, Albert J. Becker, Hartmut Vatter, Christian Henneberger
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Pathology
Hippocampal formation
Hippocampus
metabolism [Platelet Endothelial Cell Adhesion Molecule-1]
Mice
0302 clinical medicine
metabolism [Connexin 30]
Excitatory Amino Acid Agonists
Perivascular space
metabolism [Antigens]
Cellular localization
pathology [Astrocytes]
chemically induced [Epilepsy
Temporal Lobe]
chondroitin sulfate proteoglycan 4
Kainic Acid
medicine.diagnostic_test
metabolism [Proteoglycans]
ultrastructure [Cell Membrane]
Gap junction
Cell biology
Up-Regulation
Platelet Endothelial Cell Adhesion Molecule-1
medicine.anatomical_structure
Neurology
Phosphorylation
Female
Proteoglycans
Astrocyte
Subcellular Fractions
medicine.medical_specialty
pathology [Epilepsy
Temporal Lobe]
Mice
Transgenic
S100 Calcium Binding Protein beta Subunit
Biology
metabolism [Cell Membrane]
03 medical and health sciences
Cellular and Molecular Neuroscience
Western blot
Glial Fibrillary Acidic Protein
medicine
toxicity [Excitatory Amino Acid Agonists]
Connexin 30
Animals
Humans
metabolism [S100 Calcium Binding Protein beta Subunit]
ddc:610
Antigens
Hippocampal sclerosis
Cell Membrane
metabolism [Glial Fibrillary Acidic Protein]
GJB6 protein
human
medicine.disease
metabolism [Connexin 43]
physiology [Up-Regulation]
metabolism [Subcellular Fractions]
Disease Models
Animal
030104 developmental biology
pathology [Hippocampus]
Epilepsy
Temporal Lobe
Astrocytes
Connexin 43
genetics [Connexin 43]
ultrastructure [Astrocytes]
toxicity [Kainic Acid]
030217 neurology & neurosurgery
Zdroj: Glia 65(11), 1809-1820 (2017). doi:10.1002/glia.23196
ISSN: 1098-1136
DOI: 10.1002/glia.23196
Popis: 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.
Databáze: OpenAIRE
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