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Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes / J. GONCALVES in Molecular Autism, 8 (2017)
[article]
Titre : Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : J. GONCALVES, Auteur ; I. R. VIOLANTE, Auteur ; J. SERENO, Auteur ; R. A. LEITAO, Auteur ; Y. CAI, Auteur ; A. ABRUNHOSA, Auteur ; A. P. SILVA, Auteur ; A. J. SILVA, Auteur ; Miguel CASTELO-BRANCO, Auteur Article en page(s) : 47p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders Excitation/inhibition imbalance GABA(A) receptor Magnetic resonance spectroscopy Neurofibromatosis type 1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased gamma-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent. METHODS: In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1(+/-) mouse. RESULTS: Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism. CONCLUSIONS: Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found. En ligne : http://dx.doi.org/10.1186/s13229-017-0166-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 47p.[article] Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes [Texte imprimé et/ou numérique] / J. GONCALVES, Auteur ; I. R. VIOLANTE, Auteur ; J. SERENO, Auteur ; R. A. LEITAO, Auteur ; Y. CAI, Auteur ; A. ABRUNHOSA, Auteur ; A. P. SILVA, Auteur ; A. J. SILVA, Auteur ; Miguel CASTELO-BRANCO, Auteur . - 47p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 47p.
Mots-clés : Autism spectrum disorders Excitation/inhibition imbalance GABA(A) receptor Magnetic resonance spectroscopy Neurofibromatosis type 1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased gamma-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent. METHODS: In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1(+/-) mouse. RESULTS: Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism. CONCLUSIONS: Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found. En ligne : http://dx.doi.org/10.1186/s13229-017-0166-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 Right Anterior Theta Hypersynchrony as a Quantitative Measure Associated with Autistic Traits and K-Cl Cotransporter KCC2 Polymorphism / S. AYKAN in Journal of Autism and Developmental Disorders, 52-1 (January 2022)
[article]
Titre : Right Anterior Theta Hypersynchrony as a Quantitative Measure Associated with Autistic Traits and K-Cl Cotransporter KCC2 Polymorphism Type de document : Texte imprimé et/ou numérique Auteurs : S. AYKAN, Auteur ; M. H. PUGLIA, Auteur ; C. KALAYCIO?LU, Auteur ; Kevin A. PELPHREY, Auteur ; T. TUNCALI, Auteur ; E. NALÇACI, Auteur Article en page(s) : p.61-72 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics Autistic Disorder/genetics Electroencephalography Humans Solute Carrier Family 12, Member 2 Symporters/genetics Autistic traits Coherence Excitation/inhibition imbalance Kcc2 Quantitative traits Theta oscillations Index. décimale : PER Périodiques Résumé : Our aim was to use theta coherence as a quantitative trait to investigate the relation of the polymorphisms in NKCC1 (rs3087889) and KCC2 (rs9074) channel protein genes to autistic traits (AQ) in neurotypicals. Coherence values for candidate connection regions were calculated from eyes-closed resting EEGs in two independent groups. Hypersynchrony within the right anterior region was related to AQ in both groups (p?0.05), and variability in this hypersynchrony was related to the rs9074 polymorphism in the total group (p?0.05). In conclusion, theta hypersynchrony within the right anterior region during eyes-closed rest can be considered a quantitative measure for autistic traits. Replicating our findings in two independent populations with different backgrounds strengthens the validity of the current study. En ligne : http://dx.doi.org/10.1007/s10803-021-04924-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=454
in Journal of Autism and Developmental Disorders > 52-1 (January 2022) . - p.61-72[article] Right Anterior Theta Hypersynchrony as a Quantitative Measure Associated with Autistic Traits and K-Cl Cotransporter KCC2 Polymorphism [Texte imprimé et/ou numérique] / S. AYKAN, Auteur ; M. H. PUGLIA, Auteur ; C. KALAYCIO?LU, Auteur ; Kevin A. PELPHREY, Auteur ; T. TUNCALI, Auteur ; E. NALÇACI, Auteur . - p.61-72.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 52-1 (January 2022) . - p.61-72
Mots-clés : Autism Spectrum Disorder/genetics Autistic Disorder/genetics Electroencephalography Humans Solute Carrier Family 12, Member 2 Symporters/genetics Autistic traits Coherence Excitation/inhibition imbalance Kcc2 Quantitative traits Theta oscillations Index. décimale : PER Périodiques Résumé : Our aim was to use theta coherence as a quantitative trait to investigate the relation of the polymorphisms in NKCC1 (rs3087889) and KCC2 (rs9074) channel protein genes to autistic traits (AQ) in neurotypicals. Coherence values for candidate connection regions were calculated from eyes-closed resting EEGs in two independent groups. Hypersynchrony within the right anterior region was related to AQ in both groups (p?0.05), and variability in this hypersynchrony was related to the rs9074 polymorphism in the total group (p?0.05). In conclusion, theta hypersynchrony within the right anterior region during eyes-closed rest can be considered a quantitative measure for autistic traits. Replicating our findings in two independent populations with different backgrounds strengthens the validity of the current study. En ligne : http://dx.doi.org/10.1007/s10803-021-04924-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=454