Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin
As the peripheral sympathoadrenal axis is tightly controlled by the cortex via hypothalamus and brain stem, the central pathological features of Hunting's disease, (HD) that is, deposition of mutated huntingtin and synaptic dysfunctions, could also be expressed in adrenal chromaffin cells. To t...
| Autores: | , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/749520 |
| Acceso en línea: | https://hdl.handle.net/10486/749520 https://dx.doi.org/10.1111/jnc.14585 |
| Access Level: | acceso abierto |
| Palabra clave: | R6/1 mice Huntington’s disease chromaffin cells exocytosis and mutated huntingtin Farmacia Medicina |
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Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtinMartínez Ramírez, CarmenBaraibar, Andrés M.Pérez de Nanclares Fernández, CarmenMéndez López, IagoGómez, AnaMuñoz, María PazGarcía de Diego, Antonio MiguelGandía Juan, LuisCasarejos, María JoséGarcía García, AntonioR6/1 miceHuntington’s diseasechromaffin cellsexocytosis and mutated huntingtinFarmaciaMedicinaAs the peripheral sympathoadrenal axis is tightly controlled by the cortex via hypothalamus and brain stem, the central pathological features of Hunting's disease, (HD) that is, deposition of mutated huntingtin and synaptic dysfunctions, could also be expressed in adrenal chromaffin cells. To test this hypothesis we here present a thorough investigation on the pathological and functional changes undergone by chromaffin cells (CCs) from 2-month (2 m) to 7-month (7 m) aged wild-type (WT) and R6/1 mouse model of Huntington's disease (HD), stimulated with acetylcholine (ACh) or high [K+] (K+). In order to do this, we used different techniques such as inmunohistochemistry, patch-clamp, and amperometric recording. With respect to WT cells, some of the changes next summarized were already observed in HD mice at a pre-disease stage (2 m); however, they were more pronounced at 7 m when motor deficits were clearly established, as follows: (i) huntingtin over-expression as nuclear aggregates in CCs; (ii) smaller CC size with decreased dopamine β-hydroxylase expression, indicating lesser number of chromaffin secretory vesicles; (iii) reduced adrenal tissue catecholamine content; (iv) reduced Na+ currents with (v) membrane hyperpolarization and reduced ACh-evoked action potentials; (v) reduced [Ca2+]c transients with faster Ca2+ clearance; (vi) diminished quantal secretion with smaller vesicle quantal size; (vii) faster kinetics of the exocytotic fusion pore, pore expansion, and closure. On the basis of these data, the hypothesis is here raised in the sense that nuclear deposition of mutated huntingtin in adrenal CCs of R6/1 mice could be primarily responsible for poorer Na+ channel expression and function, giving rise to profound depression of cell excitability, altered Ca2+ handling and exocytosisThis study was supported by grants from MINECO 2016-78892-R and from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement No 766124 to Antonio G. Garcia. We thank the continued support of Fundación Teófilo Hernando as well as the support of Cátedra CABICYC UAM-Bioibérica and Cátedra Nutrinfant UAM-AlterWileyDepartamento de FarmacologíaFacultad de MedicinaGobierno de EspañaAgencia Estatal de InvestigaciónEuropean Commission20182018-09-05research articlehttp://purl.org/coar/resource_type/c_2df8fbb1AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10486/749520https://dx.doi.org/10.1111/jnc.1458530182387reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7495202026-06-23T12:46:27Z |
| dc.title.none.fl_str_mv |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin |
| title |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin |
| spellingShingle |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin Martínez Ramírez, Carmen R6/1 mice Huntington’s disease chromaffin cells exocytosis and mutated huntingtin Farmacia Medicina |
| title_short |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin |
| title_full |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin |
| title_fullStr |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin |
| title_full_unstemmed |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin |
| title_sort |
Altered excitability and exocytosis in chromaffin cells from the R6/1 mouse model of Huntington's disease is linked to over-expression of mutated huntingtin |
| dc.creator.none.fl_str_mv |
Martínez Ramírez, Carmen Baraibar, Andrés M. Pérez de Nanclares Fernández, Carmen Méndez López, Iago Gómez, Ana Muñoz, María Paz García de Diego, Antonio Miguel Gandía Juan, Luis Casarejos, María José García García, Antonio |
| author |
Martínez Ramírez, Carmen |
| author_facet |
Martínez Ramírez, Carmen Baraibar, Andrés M. Pérez de Nanclares Fernández, Carmen Méndez López, Iago Gómez, Ana Muñoz, María Paz García de Diego, Antonio Miguel Gandía Juan, Luis Casarejos, María José García García, Antonio |
| author_role |
author |
| author2 |
Baraibar, Andrés M. Pérez de Nanclares Fernández, Carmen Méndez López, Iago Gómez, Ana Muñoz, María Paz García de Diego, Antonio Miguel Gandía Juan, Luis Casarejos, María José García García, Antonio |
| author2_role |
author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Departamento de Farmacología Facultad de Medicina Gobierno de España Agencia Estatal de Investigación European Commission |
| dc.subject.none.fl_str_mv |
R6/1 mice Huntington’s disease chromaffin cells exocytosis and mutated huntingtin Farmacia Medicina |
| topic |
R6/1 mice Huntington’s disease chromaffin cells exocytosis and mutated huntingtin Farmacia Medicina |
| description |
As the peripheral sympathoadrenal axis is tightly controlled by the cortex via hypothalamus and brain stem, the central pathological features of Hunting's disease, (HD) that is, deposition of mutated huntingtin and synaptic dysfunctions, could also be expressed in adrenal chromaffin cells. To test this hypothesis we here present a thorough investigation on the pathological and functional changes undergone by chromaffin cells (CCs) from 2-month (2 m) to 7-month (7 m) aged wild-type (WT) and R6/1 mouse model of Huntington's disease (HD), stimulated with acetylcholine (ACh) or high [K+] (K+). In order to do this, we used different techniques such as inmunohistochemistry, patch-clamp, and amperometric recording. With respect to WT cells, some of the changes next summarized were already observed in HD mice at a pre-disease stage (2 m); however, they were more pronounced at 7 m when motor deficits were clearly established, as follows: (i) huntingtin over-expression as nuclear aggregates in CCs; (ii) smaller CC size with decreased dopamine β-hydroxylase expression, indicating lesser number of chromaffin secretory vesicles; (iii) reduced adrenal tissue catecholamine content; (iv) reduced Na+ currents with (v) membrane hyperpolarization and reduced ACh-evoked action potentials; (v) reduced [Ca2+]c transients with faster Ca2+ clearance; (vi) diminished quantal secretion with smaller vesicle quantal size; (vii) faster kinetics of the exocytotic fusion pore, pore expansion, and closure. On the basis of these data, the hypothesis is here raised in the sense that nuclear deposition of mutated huntingtin in adrenal CCs of R6/1 mice could be primarily responsible for poorer Na+ channel expression and function, giving rise to profound depression of cell excitability, altered Ca2+ handling and exocytosis |
| publishDate |
2018 |
| dc.date.none.fl_str_mv |
2018 2018-09-05 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 AM http://purl.org/coar/version/c_ab4af688f83e57aa |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10486/749520 https://dx.doi.org/10.1111/jnc.14585 30182387 |
| url |
https://hdl.handle.net/10486/749520 https://dx.doi.org/10.1111/jnc.14585 |
| identifier_str_mv |
30182387 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
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Wiley |
| publisher.none.fl_str_mv |
Wiley |
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reponame:Biblos-e Archivo. Repositorio Institucional de la UAM instname:Universidad Autónoma de Madrid |
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Universidad Autónoma de Madrid |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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