Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

Autores
Forrest, C. M.; Khalil, O. S.; Pisar, M.; Mcnair, K.; Kornisiuk, Edgar Ernesto; Snitcofsky, Marina; Gonzalez, Nelida Noemi; Jerusalinsky, Diana Alicia; Darlington, L. G.; Stone, T. W.
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
During early brain development, N-methyl-D-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog.
Fil: Forrest, C. M.. University Of Glasgow; Reino Unido
Fil: Khalil, O. S.. University Of Glasgow; Reino Unido
Fil: Pisar, M.. University Of Glasgow; Reino Unido
Fil: Mcnair, K.. University Of Glasgow; Reino Unido
Fil: Kornisiuk, Edgar Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Snitcofsky, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Gonzalez, Nelida Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Jerusalinsky, Diana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Darlington, L. G.. Epsom General Hospital; Reino Unido
Fil: Stone, T. W.. University Of Glasgow; Reino Unido
Materia
Kynurenines
Neurodevelopment
Doublecortin
Hedgehog
D-Aspartate
Tryptophan
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/12160
Acceder
id CONICETDig_91ece9ad33cb1dbf3dbe58930bb8324d
oai_identifier_str oai:ri.conicet.gov.ar:11336/12160
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathwayForrest, C. M.Khalil, O. S.Pisar, M.Mcnair, K.Kornisiuk, Edgar ErnestoSnitcofsky, MarinaGonzalez, Nelida NoemiJerusalinsky, Diana AliciaDarlington, L. G.Stone, T. W.KynureninesNeurodevelopmentDoublecortinHedgehogD-AspartateTryptophanhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1During early brain development, N-methyl-D-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog.Fil: Forrest, C. M.. University Of Glasgow; Reino UnidoFil: Khalil, O. S.. University Of Glasgow; Reino UnidoFil: Pisar, M.. University Of Glasgow; Reino UnidoFil: Mcnair, K.. University Of Glasgow; Reino UnidoFil: Kornisiuk, Edgar Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Snitcofsky, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Gonzalez, Nelida Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Jerusalinsky, Diana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Darlington, L. G.. Epsom General Hospital; Reino UnidoFil: Stone, T. W.. University Of Glasgow; Reino UnidoElsevier2013-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/12160Forrest, C. M.; Khalil, O. S.; Pisar, M.; Mcnair, K.; Kornisiuk, Edgar Ernesto; et al.; Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway; Elsevier; Neuroscience; 254; 10-2013; 241-2590306-4522enginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuroscience.2013.09.034info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0306452213008063info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:05:09Zoai:ri.conicet.gov.ar:11336/12160instacron: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 10:05:10.197CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
title Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
spellingShingle Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
Forrest, C. M.
Kynurenines
Neurodevelopment
Doublecortin
Hedgehog
D-Aspartate
Tryptophan
title_short Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
title_full Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
title_fullStr Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
title_full_unstemmed Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
title_sort Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway
dc.creator.none.fl_str_mv Forrest, C. M.
Khalil, O. S.
Pisar, M.
Mcnair, K.
Kornisiuk, Edgar Ernesto
Snitcofsky, Marina
Gonzalez, Nelida Noemi
Jerusalinsky, Diana Alicia
Darlington, L. G.
Stone, T. W.
author Forrest, C. M.
author_facet Forrest, C. M.
Khalil, O. S.
Pisar, M.
Mcnair, K.
Kornisiuk, Edgar Ernesto
Snitcofsky, Marina
Gonzalez, Nelida Noemi
Jerusalinsky, Diana Alicia
Darlington, L. G.
Stone, T. W.
author_role author
author2 Khalil, O. S.
Pisar, M.
Mcnair, K.
Kornisiuk, Edgar Ernesto
Snitcofsky, Marina
Gonzalez, Nelida Noemi
Jerusalinsky, Diana Alicia
Darlington, L. G.
Stone, T. W.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Kynurenines
Neurodevelopment
Doublecortin
Hedgehog
D-Aspartate
Tryptophan
topic Kynurenines
Neurodevelopment
Doublecortin
Hedgehog
D-Aspartate
Tryptophan
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv During early brain development, N-methyl-D-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog.
Fil: Forrest, C. M.. University Of Glasgow; Reino Unido
Fil: Khalil, O. S.. University Of Glasgow; Reino Unido
Fil: Pisar, M.. University Of Glasgow; Reino Unido
Fil: Mcnair, K.. University Of Glasgow; Reino Unido
Fil: Kornisiuk, Edgar Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Snitcofsky, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Gonzalez, Nelida Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Jerusalinsky, Diana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Darlington, L. G.. Epsom General Hospital; Reino Unido
Fil: Stone, T. W.. University Of Glasgow; Reino Unido
description During early brain development, N-methyl-D-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog.
publishDate 2013
dc.date.none.fl_str_mv 2013-10
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/11336/12160
Forrest, C. M.; Khalil, O. S.; Pisar, M.; Mcnair, K.; Kornisiuk, Edgar Ernesto; et al.; Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway; Elsevier; Neuroscience; 254; 10-2013; 241-259
0306-4522
url http://hdl.handle.net/11336/12160
identifier_str_mv Forrest, C. M.; Khalil, O. S.; Pisar, M.; Mcnair, K.; Kornisiuk, Edgar Ernesto; et al.; Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway; Elsevier; Neuroscience; 254; 10-2013; 241-259
0306-4522
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuroscience.2013.09.034
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0306452213008063
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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
_version_ 1844613884573384704
score 13.070432

Publicaciones similares