HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory

Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuro...

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Authors: Pérez-Villegas, Eva María, Pérez-Rodríguez, Mikel, Negrete-Díaz, José V., Ruiz, Rocío, Rosa, José L., Álvarez de Toledo, Guillermo, Rodríguez-Moreno, Antonio, Armengol, José Ángel
Format: article
Status:Published version
Publication Date:2020
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/235374
Online Access:http://hdl.handle.net/10261/235374
Access Level:Open access
Keyword:Autophagy
Dendritic spines
Glutamatergic input
Hippocampus
LTP
Synapses
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dc.title.none.fl_str_mv HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
title HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
spellingShingle HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
Pérez-Villegas, Eva María
Autophagy
Dendritic spines
Glutamatergic input
Hippocampus
LTP
Synapses
title_short HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
title_full HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
title_fullStr HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
title_full_unstemmed HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
title_sort HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
dc.creator.none.fl_str_mv Pérez-Villegas, Eva María
Pérez-Rodríguez, Mikel
Negrete-Díaz, José V.
Ruiz, Rocío
Rosa, José L.
Álvarez de Toledo, Guillermo
Rodríguez-Moreno, Antonio
Armengol, José Ángel
author Pérez-Villegas, Eva María
author_facet Pérez-Villegas, Eva María
Pérez-Rodríguez, Mikel
Negrete-Díaz, José V.
Ruiz, Rocío
Rosa, José L.
Álvarez de Toledo, Guillermo
Rodríguez-Moreno, Antonio
Armengol, José Ángel
author_role author
author2 Pérez-Rodríguez, Mikel
Negrete-Díaz, José V.
Ruiz, Rocío
Rosa, José L.
Álvarez de Toledo, Guillermo
Rodríguez-Moreno, Antonio
Armengol, José Ángel
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Dirección General de Investigación Científica y Técnica, DGICT (España)
Junta de Andalucía
Consejo Nacional de Ciencia y Tecnología (México)
Universidad Pablo de Olavide
Eusko Jaurlaritza
Ministerio de Economía y Competitividad (España)
Agencia Estatal de Investigación (España)
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Autophagy
Dendritic spines
Glutamatergic input
Hippocampus
LTP
Synapses
topic Autophagy
Dendritic spines
Glutamatergic input
Hippocampus
LTP
Synapses
description Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/235374
url http://hdl.handle.net/10261/235374
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-80295-R
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dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and MemoryPérez-Villegas, Eva MaríaPérez-Rodríguez, MikelNegrete-Díaz, José V.Ruiz, RocíoRosa, José L.Álvarez de Toledo, GuillermoRodríguez-Moreno, AntonioArmengol, José ÁngelAutophagyDendritic spinesGlutamatergic inputHippocampusLTPSynapsesMutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.This work was funded by the following grants: EP-V (DGICYT BFU2011-27207 and Spanish Junta de Andalucía CTS-2257); JN-D (CONACYT postdoctoral scholarship); MP-R (Ph.D. Fellowship from the Plan Propio UPO and by a Ph.D. Fellowship from the Basque Country Government); RR (Spanish Junta de Andalucía BIO-113 and SAF2015-64171-R); JR (MINECO-AEI/FEDER, UE BFU2016-80295-R); GAT (Spanish Junta de Andalucía BIO-209 and MINECO-AEI/FEDER, UE BFU2015-64536-R); AR-M (MINECO-AEI/FEDER, UE BFU2015-68655-P and the Junta de Andalucía P11-CVI-7290); and JA (Spanish Junta de Andalucía BIO-122 and MINECO-AEI/FEDER, UE PID2019-109569GB-I00).Frontiers MediaDirección General de Investigación Científica y Técnica, DGICT (España)Junta de AndalucíaConsejo Nacional de Ciencia y Tecnología (México)Universidad Pablo de OlavideEusko JaurlaritzaMinisterio de Economía y Competitividad (España)Agencia Estatal de Investigación (España)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120202021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/235374reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-64171-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-80295-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-64536-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-68655-Pinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-109569GB-I00http://doi.org/10.3389/fnana.2020.592797Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2353742026-05-22T06:33:51Z
score 15.81155

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