Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
| Autor: | Maria Elisa Calcagnotto, Luiz E. Mello, Ivan Zipancic, Manuel Álvarez-Dolado, Marina Piquer-Gil |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Generalitat Valenciana, Andalusian Ctr Mol Biol & Regenerat Med CABIMER, CIPF, Universidade Federal de São Paulo (UNIFESP) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Telencephalon
Ganglionic eminence Interneuron Biomedical Engineering Fluorescent Antibody Technique lcsh:Medicine Hippocampus Mice Transgenic Hippocampal formation Biology Inhibitory postsynaptic potential Cell therapy Mice Epilepsy GABA Neural Stem Cells Interneurons Seizures medicine Animals gamma-Aminobutyric Acid Medial ganglionic eminence (MGE) Transplantation Cell therapies lcsh:R Cell Biology medicine.disease Disease Models Animal medicine.anatomical_structure GABAergic Saporin Neuroscience |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Repositório Institucional da UNIFESP Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP Cell Transplantation, Vol 19 (2010) |
| Popis: | 16 páginas, 8 figuras.-- Licencia Creative Commons Reconocimiento-No comercial. 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. This work was supported by grants from Spanish Ministry of Science and Innovation (SAF 07/61880 and FIS 07/0079), and the Regenerative Medicine Programme from CIPF. M.E.C. and I.Z. were recipients of Miguel Servet contract from Carlos III Institute (Spanish Ministry of Science and Innovation) and Ph.D. fellowship from Generalitat Valenciana, respectively. |
| Databáze: | OpenAIRE |
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