Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 09-03-2021

Detalhes bibliográficos
Autor: Sánchez Castillo, Carla
Tipo de documento: tese
Data de publicação:2021
País:España
Recursos:Universidad Autónoma de Madrid
Repositório:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglês
OAI Identifier:oai:repositorio.uam.es:10486/695914
Acesso em linha:http://hdl.handle.net/10486/695914
Access Level:Acceso aberto
Palavra-chave:Proteínas quinasas
Sinapsis
Cognición
Biología y Biomedicina / Biología
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spelling Role of Class IA PI3K isoforms in synaptic plasticity and cognitive functionPapel de las PI3K de clase IA en plasticidad sináptica y función cognitivaSánchez Castillo, CarlaProteínas quinasasSinapsisCogniciónBiología y Biomedicina / BiologíaTesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 09-03-2021Esta tesis tiene embargado el acceso al texto completo hasta el 09-09-2022Learning and memory are cognitive functions based on the ability of the brain to modify the existing neuronal connections by strengthening or weakening them in response to individual experience. This property is known as synaptic plasticity and albeit being extensively studied for the past decades, the underlying molecular mechanisms are still not fully understood. Class IA phosphatidylinositol 3-kinases (PI3Ks) have been shown to be required for two opposing forms of synaptic plasticity, namely long-term potentiation and depression (LTP and LTD, respectively). They are heterodimers composed of a catalytic subunit of which there are three isoforms (p110α, p110β and p110δ) and a regulatory subunit (p85). There is emerging evidence regarding the differential regulation of the catalytic subunit isoforms, which could explain the functional diversity of PI3Ks regarding their requirement for synaptic plasticity. However, the use of non-selective PI3K inhibitors and the embryonic lethality of the genetic knockouts thus far has hindered the identification of specific physiological functions of these isoforms. Here, we used adult floxed mice coupled to neuron-specific Cre expression for specifically removing either the gene corresponding to p110α or p110β (PIK3CA and PIK3CB, respectively) and to assess the differential roles of each isoform in synaptic plasticity and cognitive function. As a complementary approach, we have also used isoform-specific inhibitors and shRNA technology. Our results demonstrate that both isoforms play a role in LTP expression but only p110β is required for LTD. In addition, neuronal ablation of p110α or p110β has differential consequences on short-term synaptic plasticity and basal synaptic transmission. We have shown that p110α is required to a greater extent than p110β for neuronal architecture and is the only one required for dendritic spine maintenance. Moreover, we have found that neuronal-specific deletion of p110α or p110β in the hippocampus of floxed mice causes alterations in learning/memory and sociability. Lastly, we have identified that the functions of both isoforms are spatially segregated and the lack of each subunit has consequences on different signaling pathways. The results in this PhD thesis show that there is functional diversity between p110α and p110β. In this manner, this work contributes to the understanding of the signaling cascades that elicit the different paradigms of synaptic plasticity as well as the consequences of impaired synaptic function in the hippocampus on cognitive functionEsteban García, Jose AntonioDepartamento de Biología MolecularFacultad de CienciasUAM-CSIC. Centro de Biología Molecular Severo Ochoa (CBM)20212021-03-09doctoral thesishttp://purl.org/coar/resource_type/c_db06NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/10486/695914reponame: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:10486/6959142026-06-23T12:46:27Z
dc.title.none.fl_str_mv Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
Papel de las PI3K de clase IA en plasticidad sináptica y función cognitiva
title Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
spellingShingle Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
Sánchez Castillo, Carla
Proteínas quinasas
Sinapsis
Cognición
Biología y Biomedicina / Biología
title_short Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
title_full Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
title_fullStr Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
title_full_unstemmed Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
title_sort Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function
dc.creator.none.fl_str_mv Sánchez Castillo, Carla
author Sánchez Castillo, Carla
author_facet Sánchez Castillo, Carla
author_role author
dc.contributor.none.fl_str_mv Esteban García, Jose Antonio
Departamento de Biología Molecular
Facultad de Ciencias
UAM-CSIC. Centro de Biología Molecular Severo Ochoa (CBM)
dc.subject.none.fl_str_mv Proteínas quinasas
Sinapsis
Cognición
Biología y Biomedicina / Biología
topic Proteínas quinasas
Sinapsis
Cognición
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: 09-03-2021
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-03-09
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/10486/695914
url http://hdl.handle.net/10486/695914
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 15.300719

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