Isoform-specific roles of GSK3 in synaptic transmission and plasticity

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura:17-12-2018

Detalles Bibliográficos
Autor: Draffin, Jonathan Evan
Tipo de recurso: tesis doctoral
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:10486/686666
Acceso en línea:http://hdl.handle.net/10486/686666
Access Level:acceso abierto
Palabra clave:Alzheimer, Enfermedad de - Tratamiento
Sinapsis - Tesis doctorales
Biología y Biomedicina / Biología
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spelling Isoform-specific roles of GSK3 in synaptic transmission and plasticityDraffin, Jonathan EvanAlzheimer, Enfermedad de - TratamientoSinapsis - Tesis doctoralesBiología y Biomedicina / BiologíaTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura:17-12-2018Esta tesis tiene embargado el acceso al texto completo hasta el 17-06-2020Processes of synaptic plasticity are fundamental mechanisms by which neurons alter the strength of their connections. Such changes are likely to encode aspects of an organism’s interaction with its environment. Indeed, paradigmatic forms of plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are thought to be important molecular events during the formation and refinement of certain types of memory. Both LTP and LTD are also frequently dysregulated in pathologies of the nervous system such as Alzheimer’s disease, which may be responsible for the devastating failure of memory in this condition. Glycogen synthase kinase 3 (GSK3) is a central player in Alzheimer’s disease, and has also been shown to be required for LTD and mediate the balance between different forms of plasticity at the synapse. For these reasons, it has been considered as a therapeutic target. GSK3 exists as two isoforms, GSK3α and GSK3β, of which the importance of the α isoform has been frequently overlooked. A major unknown is which of the two GSK3 isoforms is involved in mediating LTD. Here, we specifically target the GSK3 isoforms with shRNA knockdown and novel isoform-selective drugs to dissect their roles in LTD. Using electrophysiological and live imaging approaches, we find that GSK3α, but not GSK3β, is required for LTD, and is transiently anchored in dendritic spines during LTD induction. Interestingly, we also find that the microtubule-binding protein tau, which plays key roles in Alzheimer’s disease, is required for this spine anchoring of GSK3α, and for GSK3α-induced LTD. Under conditions of synaptic activity, therefore, GSK3α induces LTD through tau. We also examined the role of GSK3 in controlling synaptic transmission under basal conditions. Surprisingly, we found that GSK3 activity is required to maintain synaptic transmission. Postsynaptic GSK3 was involved in this process, and loss of transmission following blockade of GSK3 activity was expressed postsynaptically. Both isoforms of GSK3 needed to be knocked down in the postsynapse for transmission to be depressed, implying that the activity of either isoform is able to maintain synaptic transmission. The results in this PhD thesis highlight GSK3α as a potential therapeutic target for the alleviation of memory deficits during Alzheimer’s disease, and emphasise the importance of isoform-specific targetting of GSK3 more generally, given its vital roles in fundamental synaptic functionsEsteban García, José AntonioDepartamento de Biología MolecularFacultad de CienciasCentro de Biología Molecular Severo Ochoa (CBM)20182018-12-17doctoral thesishttp://purl.org/coar/resource_type/c_db06NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/10486/686666reponame: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:10486/6866662026-06-23T12:46:27Z
dc.title.none.fl_str_mv Isoform-specific roles of GSK3 in synaptic transmission and plasticity
title Isoform-specific roles of GSK3 in synaptic transmission and plasticity
spellingShingle Isoform-specific roles of GSK3 in synaptic transmission and plasticity
Draffin, Jonathan Evan
Alzheimer, Enfermedad de - Tratamiento
Sinapsis - Tesis doctorales
Biología y Biomedicina / Biología
title_short Isoform-specific roles of GSK3 in synaptic transmission and plasticity
title_full Isoform-specific roles of GSK3 in synaptic transmission and plasticity
title_fullStr Isoform-specific roles of GSK3 in synaptic transmission and plasticity
title_full_unstemmed Isoform-specific roles of GSK3 in synaptic transmission and plasticity
title_sort Isoform-specific roles of GSK3 in synaptic transmission and plasticity
dc.creator.none.fl_str_mv Draffin, Jonathan Evan
author Draffin, Jonathan Evan
author_facet Draffin, Jonathan Evan
author_role author
dc.contributor.none.fl_str_mv Esteban García, José Antonio
Departamento de Biología Molecular
Facultad de Ciencias
Centro de Biología Molecular Severo Ochoa (CBM)
dc.subject.none.fl_str_mv Alzheimer, Enfermedad de - Tratamiento
Sinapsis - Tesis doctorales
Biología y Biomedicina / Biología
topic Alzheimer, Enfermedad de - Tratamiento
Sinapsis - Tesis doctorales
Biología y Biomedicina / Biología
description Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura:17-12-2018
publishDate 2018
dc.date.none.fl_str_mv 2018
2018-12-17
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/686666
url http://hdl.handle.net/10486/686666
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
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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