Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Outros Autores: | , , , |
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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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 |
_version_ |
1814268294113263616 |