Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans

Autores
Giunti, Sebastián; Blanco, Maria Gabriela; Rayes, Diego Hernán; de Rosa, Maria Jose
Año de publicación
2023
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Mutations in PTEN (a negative regulator of the PI3K pathway) are associated with neurodevelopmental disorders, epilepsy, and schizophrenia. Several reports suggest that an increase in the ex- citation/inhibition (E/I) ratio in the brain is a hallmark of these disor- ders. The C. elegans Neuro-Muscular system, where both excitatory (ACh) and inhibitory (GABA) neurons innervate muscles, provides a suitable model for studying E/I balance. Combining pharmacologi- cal and behavior assays, we found that daf-18 (C. elegans ortholog for PTEN) mutants are hypersensitive to cholinergic drugs, suggest- ing a deficit in GABAergic signaling. daf-18 mutants are deficient in eliciting complex movements such as the “omega turn”, a sharp turn in which the GABAergic inhibition on dorsal muscles plays a criti- cal role. Moreover, using microscopy techniques, we observed that daf-18 mutants exhibit morphological defects in GABAergic neurons (abnormal branching, and incomplete commissures). In contrast, we did not find significant differences in the morphology of cholinergic neurons. DAF-18 specific rescue in GABAergic neurons partially rescued the defective phenotypes, suggesting an autonomic role of the PI3K pathway in GABAergic function. In addition, we found that the GABAergic deficit in daf-18 mutants is entirely dependent on the inactivation of the transcription factor DAF-16/FOXO. Ketogenic Diets have been used for refractory epilepsy. The mechanisms un- derlying this therapeutic effect remain elusive. We found that expo- sure to the ketone body hydroxybutyrate (βHB) during early devel- opment ameliorated GABA defects in daf-18 mutants. Interestingly, this ketone body does not alleviate the defects observed in daf-16/ FOXO mutants, suggesting an essential role of this transcription factor in the βHB effect. Since fundamental processes are highly conserved throughout the animal kingdom, this study may contribute to the understanding of disorders associated with E/I imbalances in mammals.
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: 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
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
Reunión Conjunta LXVIII Reunión Anual De La Sociedad Argentina De Investigación Clínica; XXV Jornadas Anuales De La Sociedad Argentina De Biología; LV Reunión Anual De La Asociación Argentina De Farmacología Experimental; VIII Reunión Científica Regional De La Asociación Argentina De Ciencia Y Tecnología De Animales De Laboratorio
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Biología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Materia
C. ELEGANS
KETONE BODIES
PTEN
GABAergic NEURONS
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:11336/262865
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegansGiunti, SebastiánBlanco, Maria GabrielaRayes, Diego Hernánde Rosa, Maria JoseC. ELEGANSKETONE BODIESPTENGABAergic NEURONShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Mutations in PTEN (a negative regulator of the PI3K pathway) are associated with neurodevelopmental disorders, epilepsy, and schizophrenia. Several reports suggest that an increase in the ex- citation/inhibition (E/I) ratio in the brain is a hallmark of these disor- ders. The C. elegans Neuro-Muscular system, where both excitatory (ACh) and inhibitory (GABA) neurons innervate muscles, provides a suitable model for studying E/I balance. Combining pharmacologi- cal and behavior assays, we found that daf-18 (C. elegans ortholog for PTEN) mutants are hypersensitive to cholinergic drugs, suggest- ing a deficit in GABAergic signaling. daf-18 mutants are deficient in eliciting complex movements such as the “omega turn”, a sharp turn in which the GABAergic inhibition on dorsal muscles plays a criti- cal role. Moreover, using microscopy techniques, we observed that daf-18 mutants exhibit morphological defects in GABAergic neurons (abnormal branching, and incomplete commissures). In contrast, we did not find significant differences in the morphology of cholinergic neurons. DAF-18 specific rescue in GABAergic neurons partially rescued the defective phenotypes, suggesting an autonomic role of the PI3K pathway in GABAergic function. In addition, we found that the GABAergic deficit in daf-18 mutants is entirely dependent on the inactivation of the transcription factor DAF-16/FOXO. Ketogenic Diets have been used for refractory epilepsy. The mechanisms un- derlying this therapeutic effect remain elusive. We found that expo- sure to the ketone body hydroxybutyrate (βHB) during early devel- opment ameliorated GABA defects in daf-18 mutants. Interestingly, this ketone body does not alleviate the defects observed in daf-16/ FOXO mutants, suggesting an essential role of this transcription factor in the βHB effect. Since fundamental processes are highly conserved throughout the animal kingdom, this study may contribute to the understanding of disorders associated with E/I imbalances in mammals.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: 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; 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; ArgentinaReunión Conjunta LXVIII Reunión Anual De La Sociedad Argentina De Investigación Clínica; XXV Jornadas Anuales De La Sociedad Argentina De Biología; LV Reunión Anual De La Asociación Argentina De Farmacología Experimental; VIII Reunión Científica Regional De La Asociación Argentina De Ciencia Y Tecnología De Animales De LaboratorioMar del PlataArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de BiologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de Ciencia y Tecnología de Animales de LaboratorioFundación Revista MedicinaLuthy, Isabel AliciaPerez Martinez, Silvina LauraSimonovich, VenturaPinto, Gabriel2023info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/262865Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans; Reunión Conjunta LXVIII Reunión Anual De La Sociedad Argentina De Investigación Clínica; XXV Jornadas Anuales De La Sociedad Argentina De Biología; LV Reunión Anual De La Asociación Argentina De Farmacología Experimental; VIII Reunión Científica Regional De La Asociación Argentina De Ciencia Y Tecnología De Animales De Laboratorio; Mar del Plata; Argentina; 2023; 224-2250025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicinainfo:eu-repo/semantics/altIdentifier/url/https://www.reunionbiociencias.com.ar/wp-content/uploads/2023/11/Revista-Medicina-2023.pdfNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:51:38Zoai:ri.conicet.gov.ar:11336/262865instacron: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 09:51:38.401CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
title Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
spellingShingle Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
Giunti, Sebastián
C. ELEGANS
KETONE BODIES
PTEN
GABAergic NEURONS
title_short Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
title_full Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
title_fullStr Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
title_full_unstemmed Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
title_sort Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans
dc.creator.none.fl_str_mv Giunti, Sebastián
Blanco, Maria Gabriela
Rayes, Diego Hernán
de Rosa, Maria Jose
author Giunti, Sebastián
author_facet Giunti, Sebastián
Blanco, Maria Gabriela
Rayes, Diego Hernán
de Rosa, Maria Jose
author_role author
author2 Blanco, Maria Gabriela
Rayes, Diego Hernán
de Rosa, Maria Jose
author2_role author
author
author
dc.contributor.none.fl_str_mv Luthy, Isabel Alicia
Perez Martinez, Silvina Laura
Simonovich, Ventura
Pinto, Gabriel
dc.subject.none.fl_str_mv C. ELEGANS
KETONE BODIES
PTEN
GABAergic NEURONS
topic C. ELEGANS
KETONE BODIES
PTEN
GABAergic NEURONS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Mutations in PTEN (a negative regulator of the PI3K pathway) are associated with neurodevelopmental disorders, epilepsy, and schizophrenia. Several reports suggest that an increase in the ex- citation/inhibition (E/I) ratio in the brain is a hallmark of these disor- ders. The C. elegans Neuro-Muscular system, where both excitatory (ACh) and inhibitory (GABA) neurons innervate muscles, provides a suitable model for studying E/I balance. Combining pharmacologi- cal and behavior assays, we found that daf-18 (C. elegans ortholog for PTEN) mutants are hypersensitive to cholinergic drugs, suggest- ing a deficit in GABAergic signaling. daf-18 mutants are deficient in eliciting complex movements such as the “omega turn”, a sharp turn in which the GABAergic inhibition on dorsal muscles plays a criti- cal role. Moreover, using microscopy techniques, we observed that daf-18 mutants exhibit morphological defects in GABAergic neurons (abnormal branching, and incomplete commissures). In contrast, we did not find significant differences in the morphology of cholinergic neurons. DAF-18 specific rescue in GABAergic neurons partially rescued the defective phenotypes, suggesting an autonomic role of the PI3K pathway in GABAergic function. In addition, we found that the GABAergic deficit in daf-18 mutants is entirely dependent on the inactivation of the transcription factor DAF-16/FOXO. Ketogenic Diets have been used for refractory epilepsy. The mechanisms un- derlying this therapeutic effect remain elusive. We found that expo- sure to the ketone body hydroxybutyrate (βHB) during early devel- opment ameliorated GABA defects in daf-18 mutants. Interestingly, this ketone body does not alleviate the defects observed in daf-16/ FOXO mutants, suggesting an essential role of this transcription factor in the βHB effect. Since fundamental processes are highly conserved throughout the animal kingdom, this study may contribute to the understanding of disorders associated with E/I imbalances in mammals.
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: 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
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
Reunión Conjunta LXVIII Reunión Anual De La Sociedad Argentina De Investigación Clínica; XXV Jornadas Anuales De La Sociedad Argentina De Biología; LV Reunión Anual De La Asociación Argentina De Farmacología Experimental; VIII Reunión Científica Regional De La Asociación Argentina De Ciencia Y Tecnología De Animales De Laboratorio
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Biología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
description Mutations in PTEN (a negative regulator of the PI3K pathway) are associated with neurodevelopmental disorders, epilepsy, and schizophrenia. Several reports suggest that an increase in the ex- citation/inhibition (E/I) ratio in the brain is a hallmark of these disor- ders. The C. elegans Neuro-Muscular system, where both excitatory (ACh) and inhibitory (GABA) neurons innervate muscles, provides a suitable model for studying E/I balance. Combining pharmacologi- cal and behavior assays, we found that daf-18 (C. elegans ortholog for PTEN) mutants are hypersensitive to cholinergic drugs, suggest- ing a deficit in GABAergic signaling. daf-18 mutants are deficient in eliciting complex movements such as the “omega turn”, a sharp turn in which the GABAergic inhibition on dorsal muscles plays a criti- cal role. Moreover, using microscopy techniques, we observed that daf-18 mutants exhibit morphological defects in GABAergic neurons (abnormal branching, and incomplete commissures). In contrast, we did not find significant differences in the morphology of cholinergic neurons. DAF-18 specific rescue in GABAergic neurons partially rescued the defective phenotypes, suggesting an autonomic role of the PI3K pathway in GABAergic function. In addition, we found that the GABAergic deficit in daf-18 mutants is entirely dependent on the inactivation of the transcription factor DAF-16/FOXO. Ketogenic Diets have been used for refractory epilepsy. The mechanisms un- derlying this therapeutic effect remain elusive. We found that expo- sure to the ketone body hydroxybutyrate (βHB) during early devel- opment ameliorated GABA defects in daf-18 mutants. Interestingly, this ketone body does not alleviate the defects observed in daf-16/ FOXO mutants, suggesting an essential role of this transcription factor in the βHB effect. Since fundamental processes are highly conserved throughout the animal kingdom, this study may contribute to the understanding of disorders associated with E/I imbalances in mammals.
publishDate 2023
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dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/262865
Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans; Reunión Conjunta LXVIII Reunión Anual De La Sociedad Argentina De Investigación Clínica; XXV Jornadas Anuales De La Sociedad Argentina De Biología; LV Reunión Anual De La Asociación Argentina De Farmacología Experimental; VIII Reunión Científica Regional De La Asociación Argentina De Ciencia Y Tecnología De Animales De Laboratorio; Mar del Plata; Argentina; 2023; 224-225
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/262865
identifier_str_mv Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans; Reunión Conjunta LXVIII Reunión Anual De La Sociedad Argentina De Investigación Clínica; XXV Jornadas Anuales De La Sociedad Argentina De Biología; LV Reunión Anual De La Asociación Argentina De Farmacología Experimental; VIII Reunión Científica Regional De La Asociación Argentina De Ciencia Y Tecnología De Animales De Laboratorio; Mar del Plata; Argentina; 2023; 224-225
0025-7680
1669-9106
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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publisher.none.fl_str_mv Fundación Revista Medicina
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