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Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas

Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron netwo...

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Autores principales: Wu, Jie, Gao, Ming, Rice, Stephen G., Tsang, Candy, Beggs, John, Turner, Dharshaun, Li, Guohui, Yang, Bo, Xia, Kunkun, Gao, Fenfei, Qiu, Shenfeng, Liu, Qiang, Kerrigan, John F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919609/
https://www.ncbi.nlm.nih.gov/pubmed/27428422
http://dx.doi.org/10.1016/j.ebiom.2016.04.026
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author Wu, Jie
Gao, Ming
Rice, Stephen G.
Tsang, Candy
Beggs, John
Turner, Dharshaun
Li, Guohui
Yang, Bo
Xia, Kunkun
Gao, Fenfei
Qiu, Shenfeng
Liu, Qiang
Kerrigan, John F.
author_facet Wu, Jie
Gao, Ming
Rice, Stephen G.
Tsang, Candy
Beggs, John
Turner, Dharshaun
Li, Guohui
Yang, Bo
Xia, Kunkun
Gao, Fenfei
Qiu, Shenfeng
Liu, Qiang
Kerrigan, John F.
author_sort Wu, Jie
collection PubMed
description Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patient's HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients.
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spelling pubmed-49196092016-06-30 Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas Wu, Jie Gao, Ming Rice, Stephen G. Tsang, Candy Beggs, John Turner, Dharshaun Li, Guohui Yang, Bo Xia, Kunkun Gao, Fenfei Qiu, Shenfeng Liu, Qiang Kerrigan, John F. EBioMedicine Research Paper Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patient's HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients. Elsevier 2016-04-22 /pmc/articles/PMC4919609/ /pubmed/27428422 http://dx.doi.org/10.1016/j.ebiom.2016.04.026 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Wu, Jie
Gao, Ming
Rice, Stephen G.
Tsang, Candy
Beggs, John
Turner, Dharshaun
Li, Guohui
Yang, Bo
Xia, Kunkun
Gao, Fenfei
Qiu, Shenfeng
Liu, Qiang
Kerrigan, John F.
Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas
title Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas
title_full Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas
title_fullStr Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas
title_full_unstemmed Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas
title_short Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas
title_sort gap junctions contribute to ictal/interictal genesis in human hypothalamic hamartomas
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919609/
https://www.ncbi.nlm.nih.gov/pubmed/27428422
http://dx.doi.org/10.1016/j.ebiom.2016.04.026
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