Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility

Detalhes bibliográficos
Autor(a) principal: Zipancic, I.
Data de Publicação: 2010
Outros Autores: Calcagnotto, M. E., Piquer-Gil, M., Mello, Luiz Eugenio Araujo de Moraes [UNIFESP], Alvarez-Dolado, M.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNIFESP
Texto Completo: http://dx.doi.org/10.3727/096368910X491383
http://repositorio.unifesp.br/handle/11600/32054
Resumo: Defects in GABAergic function can cause epilepsy. in the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP(+) MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.
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spelling Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure SusceptibilityCell therapyGABAEpilepsyInterneuronMedial ganglionic eminence (MGE)SaporinDefects in GABAergic function can cause epilepsy. in the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP(+) MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.Andalusian Ctr Mol Biol & Regenerat Med CABIMER, Dept Cell Therapy & Regenerat Med, Seville, SpainCIPF, Valencia, SpainUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilWeb of ScienceSpanish Ministry of Science and InnovationCIPFCarlos III Institute (Spanish Ministry of Science and Innovation)Generalitat ValencianaSpanish Ministry of Science and Innovation: SAF 07/61880Spanish Ministry of Science and Innovation: FIS 07/0079Cognizant Communication CorpAndalusian Ctr Mol Biol & Regenerat Med CABIMERCIPFUniversidade Federal de São Paulo (UNIFESP)Zipancic, I.Calcagnotto, M. E.Piquer-Gil, M.Mello, Luiz Eugenio Araujo de Moraes [UNIFESP]Alvarez-Dolado, M.2016-01-24T13:59:02Z2016-01-24T13:59:02Z2010-01-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion549-564application/pdfhttp://dx.doi.org/10.3727/096368910X491383Cell Transplantation. Elmsford: Cognizant Communication Corp, v. 19, n. 5, p. 549-564, 2010.10.3727/096368910X491383WOS000280257200005.pdf0963-6897http://repositorio.unifesp.br/handle/11600/32054WOS:000280257200005engCell Transplantationinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP2024-08-07T22:03:06Zoai:repositorio.unifesp.br/:11600/32054Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestbiblioteca.csp@unifesp.bropendoar:34652024-08-07T22:03:06Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false
dc.title.none.fl_str_mv Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
title Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
spellingShingle Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
Zipancic, I.
Cell therapy
GABA
Epilepsy
Interneuron
Medial ganglionic eminence (MGE)
Saporin
title_short Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
title_full Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
title_fullStr Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
title_full_unstemmed Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
title_sort Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
author Zipancic, I.
author_facet Zipancic, I.
Calcagnotto, M. E.
Piquer-Gil, M.
Mello, Luiz Eugenio Araujo de Moraes [UNIFESP]
Alvarez-Dolado, M.
author_role author
author2 Calcagnotto, M. E.
Piquer-Gil, M.
Mello, Luiz Eugenio Araujo de Moraes [UNIFESP]
Alvarez-Dolado, M.
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Andalusian Ctr Mol Biol & Regenerat Med CABIMER
CIPF
Universidade Federal de São Paulo (UNIFESP)
dc.contributor.author.fl_str_mv Zipancic, I.
Calcagnotto, M. E.
Piquer-Gil, M.
Mello, Luiz Eugenio Araujo de Moraes [UNIFESP]
Alvarez-Dolado, M.
dc.subject.por.fl_str_mv Cell therapy
GABA
Epilepsy
Interneuron
Medial ganglionic eminence (MGE)
Saporin
topic Cell therapy
GABA
Epilepsy
Interneuron
Medial ganglionic eminence (MGE)
Saporin
description Defects in GABAergic function can cause epilepsy. in the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP(+) MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.
publishDate 2010
dc.date.none.fl_str_mv 2010-01-01
2016-01-24T13:59:02Z
2016-01-24T13:59:02Z
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.3727/096368910X491383
Cell Transplantation. Elmsford: Cognizant Communication Corp, v. 19, n. 5, p. 549-564, 2010.
10.3727/096368910X491383
WOS000280257200005.pdf
0963-6897
http://repositorio.unifesp.br/handle/11600/32054
WOS:000280257200005
url http://dx.doi.org/10.3727/096368910X491383
http://repositorio.unifesp.br/handle/11600/32054
identifier_str_mv Cell Transplantation. Elmsford: Cognizant Communication Corp, v. 19, n. 5, p. 549-564, 2010.
10.3727/096368910X491383
WOS000280257200005.pdf
0963-6897
WOS:000280257200005
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Cell Transplantation
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 549-564
application/pdf
dc.publisher.none.fl_str_mv Cognizant Communication Corp
publisher.none.fl_str_mv Cognizant Communication Corp
dc.source.none.fl_str_mv reponame:Repositório Institucional da UNIFESP
instname:Universidade Federal de São Paulo (UNIFESP)
instacron:UNIFESP
instname_str Universidade Federal de São Paulo (UNIFESP)
instacron_str UNIFESP
institution UNIFESP
reponame_str Repositório Institucional da UNIFESP
collection Repositório Institucional da UNIFESP
repository.name.fl_str_mv Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)
repository.mail.fl_str_mv biblioteca.csp@unifesp.br
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