Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

Autores
Codagnone, Martín Gabriel; Kara, Nirit; Ratsika, Anna; Rocha Levone, Brunno; van de Wouw, Marcel; Tan, Laura A.; Cunningham, Jacobi I.; Sanchez, Connie; Cryan, John F.; O'Leary, Olivia F.
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.
Fil: Codagnone, Martín Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina
Fil: Kara, Nirit. University College Cork; Irlanda
Fil: Ratsika, Anna. University College Cork; Irlanda
Fil: Rocha Levone, Brunno. University College Cork; Irlanda
Fil: van de Wouw, Marcel. University College Cork; Irlanda
Fil: Tan, Laura A.. No especifíca;
Fil: Cunningham, Jacobi I.. No especifíca;
Fil: Sanchez, Connie. No especifíca;
Fil: Cryan, John F.. University College Cork; Irlanda
Fil: O'Leary, Olivia F.. University College Cork; Irlanda
Materia
STRESS
FKBP51
SAFIT2
NEUROGENESIS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/214891
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/214891
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesisCodagnone, Martín GabrielKara, NiritRatsika, AnnaRocha Levone, Brunnovan de Wouw, MarcelTan, Laura A.Cunningham, Jacobi I.Sanchez, ConnieCryan, John F.O'Leary, Olivia F.STRESSFKBP51SAFIT2NEUROGENESIShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.Fil: Codagnone, Martín Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Kara, Nirit. University College Cork; IrlandaFil: Ratsika, Anna. University College Cork; IrlandaFil: Rocha Levone, Brunno. University College Cork; IrlandaFil: van de Wouw, Marcel. University College Cork; IrlandaFil: Tan, Laura A.. No especifíca;Fil: Cunningham, Jacobi I.. No especifíca;Fil: Sanchez, Connie. No especifíca;Fil: Cryan, John F.. University College Cork; IrlandaFil: O'Leary, Olivia F.. University College Cork; IrlandaNature Publishing Group2022-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/214891Codagnone, Martín Gabriel; Kara, Nirit; Ratsika, Anna; Rocha Levone, Brunno; van de Wouw, Marcel; et al.; Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis; Nature Publishing Group; Molecular Psychiatry; 9-2022; 1-111359-4184CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41380-022-01755-9info:eu-repo/semantics/altIdentifier/doi/10.1038/s41380-022-01755-9info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:55:15Zoai:ri.conicet.gov.ar:11336/214891instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:55:15.574CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
title Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
spellingShingle Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
Codagnone, Martín Gabriel
STRESS
FKBP51
SAFIT2
NEUROGENESIS
title_short Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
title_full Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
title_fullStr Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
title_full_unstemmed Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
title_sort Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis
dc.creator.none.fl_str_mv Codagnone, Martín Gabriel
Kara, Nirit
Ratsika, Anna
Rocha Levone, Brunno
van de Wouw, Marcel
Tan, Laura A.
Cunningham, Jacobi I.
Sanchez, Connie
Cryan, John F.
O'Leary, Olivia F.
author Codagnone, Martín Gabriel
author_facet Codagnone, Martín Gabriel
Kara, Nirit
Ratsika, Anna
Rocha Levone, Brunno
van de Wouw, Marcel
Tan, Laura A.
Cunningham, Jacobi I.
Sanchez, Connie
Cryan, John F.
O'Leary, Olivia F.
author_role author
author2 Kara, Nirit
Ratsika, Anna
Rocha Levone, Brunno
van de Wouw, Marcel
Tan, Laura A.
Cunningham, Jacobi I.
Sanchez, Connie
Cryan, John F.
O'Leary, Olivia F.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv STRESS
FKBP51
SAFIT2
NEUROGENESIS
topic STRESS
FKBP51
SAFIT2
NEUROGENESIS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.
Fil: Codagnone, Martín Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina
Fil: Kara, Nirit. University College Cork; Irlanda
Fil: Ratsika, Anna. University College Cork; Irlanda
Fil: Rocha Levone, Brunno. University College Cork; Irlanda
Fil: van de Wouw, Marcel. University College Cork; Irlanda
Fil: Tan, Laura A.. No especifíca;
Fil: Cunningham, Jacobi I.. No especifíca;
Fil: Sanchez, Connie. No especifíca;
Fil: Cryan, John F.. University College Cork; Irlanda
Fil: O'Leary, Olivia F.. University College Cork; Irlanda
description Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.
publishDate 2022
dc.date.none.fl_str_mv 2022-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/214891
Codagnone, Martín Gabriel; Kara, Nirit; Ratsika, Anna; Rocha Levone, Brunno; van de Wouw, Marcel; et al.; Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis; Nature Publishing Group; Molecular Psychiatry; 9-2022; 1-11
1359-4184
CONICET Digital
CONICET
url http://hdl.handle.net/11336/214891
identifier_str_mv Codagnone, Martín Gabriel; Kara, Nirit; Ratsika, Anna; Rocha Levone, Brunno; van de Wouw, Marcel; et al.; Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis; Nature Publishing Group; Molecular Psychiatry; 9-2022; 1-11
1359-4184
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41380-022-01755-9
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41380-022-01755-9
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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