The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants

Autores
Giunti, Sebastián; Blanco, Maria Gabriela; de Rosa, Maria Jose; Rayes, Diego Hernán
Año de publicación
2023
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
An increased Excitation/Inhibition (E/I) ratio in the brain is a hallmark of neurological disorders such as Autism Spectrum Disorder (ASD). Mutations in PTEN, a gene that encodes for the main negative regulator of the conserved PI3K/AKT pathway, are strongly associated with ASD. However, it is unclear how PTEN deficiencies can lead to E/I disequilibrium. The C. elegans neuromuscular system, where both excitatory (Cholinergic) and inhibitory (GABAergic) motor neurons regulate muscle activity, provides a proven simple model for studying E/I balance. We found that mutants in daf-18 (ortholog for PTEN) exhibit phenotypes typical of animals with deficient GABAergic signaling. While cholinergic neuron morphology is normal, we observed defects that occur specifically in GABAergic neurites. This selective impairment accounts for the disruption of the E/I balance in daf-18 mutants. In addition, we showed that the low activity of the transcription factor DAF-16 (ortholog for FOXO3A) during GABAergic neurodevelopment arises for the behavioral defects in daf-18 mutants. Ketogenic Diets (KGDs), in which the production of ketone bodies (KBs) is forced, have been established as an effective treatment for disorders associated with E/I imbalances. The mechanisms underlying its effect are not understood. We found that exposure to the KB hydroxybutyrate (βHB) during early development improves GABAergic neurodevelopment in daf-18 mutants. This effect depends on DAF-16/FOXO. Since the PI3K/ AKT pathway is highly conserved, this study may provide universal information on the proven link between PTEN mutations and neurodevelopmental defects and, equally important, the mechanisms underlying KGDs positive effects on neuronal disorders characterized by E/I imbalance.
Fil: Giunti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Blanco, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
24th International C. elegans Conference
Glasgow
Reino Unido
Genetics Society of America
Materia
ELEGANS
KETOGENIC
GABAERGIC
NEURODEVELOPMENT
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/229147
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/229147
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutantsGiunti, SebastiánBlanco, Maria Gabrielade Rosa, Maria JoseRayes, Diego HernánELEGANSKETOGENICGABAERGICNEURODEVELOPMENThttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1An increased Excitation/Inhibition (E/I) ratio in the brain is a hallmark of neurological disorders such as Autism Spectrum Disorder (ASD). Mutations in PTEN, a gene that encodes for the main negative regulator of the conserved PI3K/AKT pathway, are strongly associated with ASD. However, it is unclear how PTEN deficiencies can lead to E/I disequilibrium. The C. elegans neuromuscular system, where both excitatory (Cholinergic) and inhibitory (GABAergic) motor neurons regulate muscle activity, provides a proven simple model for studying E/I balance. We found that mutants in daf-18 (ortholog for PTEN) exhibit phenotypes typical of animals with deficient GABAergic signaling. While cholinergic neuron morphology is normal, we observed defects that occur specifically in GABAergic neurites. This selective impairment accounts for the disruption of the E/I balance in daf-18 mutants. In addition, we showed that the low activity of the transcription factor DAF-16 (ortholog for FOXO3A) during GABAergic neurodevelopment arises for the behavioral defects in daf-18 mutants. Ketogenic Diets (KGDs), in which the production of ketone bodies (KBs) is forced, have been established as an effective treatment for disorders associated with E/I imbalances. The mechanisms underlying its effect are not understood. We found that exposure to the KB hydroxybutyrate (βHB) during early development improves GABAergic neurodevelopment in daf-18 mutants. This effect depends on DAF-16/FOXO. Since the PI3K/ AKT pathway is highly conserved, this study may provide universal information on the proven link between PTEN mutations and neurodevelopmental defects and, equally important, the mechanisms underlying KGDs positive effects on neuronal disorders characterized by E/I imbalance.Fil: Giunti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Blanco, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina24th International C. elegans ConferenceGlasgowReino UnidoGenetics Society of AmericaGenetics Society of America2023info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectConferenciaBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/229147The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants; 24th International C. elegans Conference; Glasgow; Reino Unido; 2023; 392-392CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://genetics-gsa.org/celegans2023/program-and-abstract-books/Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:56Zoai:ri.conicet.gov.ar:11336/229147instacron: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:34982025-09-03 10:09:56.8CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
title The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
spellingShingle The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
Giunti, Sebastián
ELEGANS
KETOGENIC
GABAERGIC
NEURODEVELOPMENT
title_short The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
title_full The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
title_fullStr The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
title_full_unstemmed The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
title_sort The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants
dc.creator.none.fl_str_mv Giunti, Sebastián
Blanco, Maria Gabriela
de Rosa, Maria Jose
Rayes, Diego Hernán
author Giunti, Sebastián
author_facet Giunti, Sebastián
Blanco, Maria Gabriela
de Rosa, Maria Jose
Rayes, Diego Hernán
author_role author
author2 Blanco, Maria Gabriela
de Rosa, Maria Jose
Rayes, Diego Hernán
author2_role author
author
author
dc.subject.none.fl_str_mv ELEGANS
KETOGENIC
GABAERGIC
NEURODEVELOPMENT
topic ELEGANS
KETOGENIC
GABAERGIC
NEURODEVELOPMENT
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv An increased Excitation/Inhibition (E/I) ratio in the brain is a hallmark of neurological disorders such as Autism Spectrum Disorder (ASD). Mutations in PTEN, a gene that encodes for the main negative regulator of the conserved PI3K/AKT pathway, are strongly associated with ASD. However, it is unclear how PTEN deficiencies can lead to E/I disequilibrium. The C. elegans neuromuscular system, where both excitatory (Cholinergic) and inhibitory (GABAergic) motor neurons regulate muscle activity, provides a proven simple model for studying E/I balance. We found that mutants in daf-18 (ortholog for PTEN) exhibit phenotypes typical of animals with deficient GABAergic signaling. While cholinergic neuron morphology is normal, we observed defects that occur specifically in GABAergic neurites. This selective impairment accounts for the disruption of the E/I balance in daf-18 mutants. In addition, we showed that the low activity of the transcription factor DAF-16 (ortholog for FOXO3A) during GABAergic neurodevelopment arises for the behavioral defects in daf-18 mutants. Ketogenic Diets (KGDs), in which the production of ketone bodies (KBs) is forced, have been established as an effective treatment for disorders associated with E/I imbalances. The mechanisms underlying its effect are not understood. We found that exposure to the KB hydroxybutyrate (βHB) during early development improves GABAergic neurodevelopment in daf-18 mutants. This effect depends on DAF-16/FOXO. Since the PI3K/ AKT pathway is highly conserved, this study may provide universal information on the proven link between PTEN mutations and neurodevelopmental defects and, equally important, the mechanisms underlying KGDs positive effects on neuronal disorders characterized by E/I imbalance.
Fil: Giunti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Blanco, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
24th International C. elegans Conference
Glasgow
Reino Unido
Genetics Society of America
description An increased Excitation/Inhibition (E/I) ratio in the brain is a hallmark of neurological disorders such as Autism Spectrum Disorder (ASD). Mutations in PTEN, a gene that encodes for the main negative regulator of the conserved PI3K/AKT pathway, are strongly associated with ASD. However, it is unclear how PTEN deficiencies can lead to E/I disequilibrium. The C. elegans neuromuscular system, where both excitatory (Cholinergic) and inhibitory (GABAergic) motor neurons regulate muscle activity, provides a proven simple model for studying E/I balance. We found that mutants in daf-18 (ortholog for PTEN) exhibit phenotypes typical of animals with deficient GABAergic signaling. While cholinergic neuron morphology is normal, we observed defects that occur specifically in GABAergic neurites. This selective impairment accounts for the disruption of the E/I balance in daf-18 mutants. In addition, we showed that the low activity of the transcription factor DAF-16 (ortholog for FOXO3A) during GABAergic neurodevelopment arises for the behavioral defects in daf-18 mutants. Ketogenic Diets (KGDs), in which the production of ketone bodies (KBs) is forced, have been established as an effective treatment for disorders associated with E/I imbalances. The mechanisms underlying its effect are not understood. We found that exposure to the KB hydroxybutyrate (βHB) during early development improves GABAergic neurodevelopment in daf-18 mutants. This effect depends on DAF-16/FOXO. Since the PI3K/ AKT pathway is highly conserved, this study may provide universal information on the proven link between PTEN mutations and neurodevelopmental defects and, equally important, the mechanisms underlying KGDs positive effects on neuronal disorders characterized by E/I imbalance.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Conferencia
Book
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/229147
The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants; 24th International C. elegans Conference; Glasgow; Reino Unido; 2023; 392-392
CONICET Digital
CONICET
url http://hdl.handle.net/11336/229147
identifier_str_mv The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants; 24th International C. elegans Conference; Glasgow; Reino Unido; 2023; 392-392
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://genetics-gsa.org/celegans2023/program-and-abstract-books/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Genetics Society of America
publisher.none.fl_str_mv Genetics Society of America
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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