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Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism / F. S. LO in Molecular Autism, 9 (2018)
[article]
Titre : Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism Type de document : Texte imprimé et/ou numérique Auteurs : F. S. LO, Auteur ; R. S. ERZURUMLU, Auteur Article en page(s) : 13p. Langues : Anglais (eng) Mots-clés : Barrel cortex GABAA receptors Homeostatic plasticity Met receptor tyrosine kinase Pioglitazone Thalamocortical circuitry Index. décimale : PER Périodiques Résumé : Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1(cre)/Met(flox) mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1(cre)/Met(flox) mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. En ligne : http://dx.doi.org/10.1186/s13229-018-0196-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354
in Molecular Autism > 9 (2018) . - 13p.[article] Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism [Texte imprimé et/ou numérique] / F. S. LO, Auteur ; R. S. ERZURUMLU, Auteur . - 13p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 13p.
Mots-clés : Barrel cortex GABAA receptors Homeostatic plasticity Met receptor tyrosine kinase Pioglitazone Thalamocortical circuitry Index. décimale : PER Périodiques Résumé : Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1(cre)/Met(flox) mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1(cre)/Met(flox) mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. En ligne : http://dx.doi.org/10.1186/s13229-018-0196-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 Autism Risk Gene MET Variation and Cortical Thickness in Typically Developing Children and Adolescents / Alexis HEDRICK in Autism Research, 5-6 (December 2012)
[article]
Titre : Autism Risk Gene MET Variation and Cortical Thickness in Typically Developing Children and Adolescents Type de document : Texte imprimé et/ou numérique Auteurs : Alexis HEDRICK, Auteur ; Yohan LEE, Auteur ; Gregory L. WALLACE, Auteur ; Deanna GREENSTEIN, Auteur ; Liv S. CLASEN, Auteur ; Jay N. GIEDD, Auteur ; Armin RAZNAHAN, Auteur Article en page(s) : p.434-439 Mots-clés : MET receptor tyrosine kinase cortex autism development MRI Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1002/aur.1256 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=187
in Autism Research > 5-6 (December 2012) . - p.434-439[article] Autism Risk Gene MET Variation and Cortical Thickness in Typically Developing Children and Adolescents [Texte imprimé et/ou numérique] / Alexis HEDRICK, Auteur ; Yohan LEE, Auteur ; Gregory L. WALLACE, Auteur ; Deanna GREENSTEIN, Auteur ; Liv S. CLASEN, Auteur ; Jay N. GIEDD, Auteur ; Armin RAZNAHAN, Auteur . - p.434-439.
in Autism Research > 5-6 (December 2012) . - p.434-439
Mots-clés : MET receptor tyrosine kinase cortex autism development MRI Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1002/aur.1256 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=187