Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior / Barbara L. THOMPSON in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.35 Titre : Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior Type de document : texte imprimé Auteurs : Barbara L. THOMPSON, Auteur ; Pat LEVITT, Auteur Article en page(s) : p.35 Langues : Anglais (eng) Mots-clés : Autism  Behavior  Fear learning  Gene dose  Met  Mouse  Phenotype Index. décimale : PER Périodiques Résumé : BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity. En ligne : http://dx.doi.org/10.1186/s11689-015-9131-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior [texte imprimé] / Barbara L. THOMPSON, Auteur ; Pat LEVITT, Auteur . - p.35. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.35 Mots-clés : Autism  Behavior  Fear learning  Gene dose  Met  Mouse  Phenotype Index. décimale : PER Périodiques Résumé : BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity. En ligne : http://dx.doi.org/10.1186/s11689-015-9131-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Pleiotropic Effects of Neurotransmission during Development: Modulators of Modularity / Barbara L. THOMPSON in Journal of Autism and Developmental Disorders, 39-2 (February 2009)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 39-2 (February 2009) . - p.260-268 Titre : Pleiotropic Effects of Neurotransmission during Development: Modulators of Modularity Type de document : texte imprimé Auteurs : Barbara L. THOMPSON, Auteur ; Gregg D. STANWOOD, Auteur Année de publication : 2009 Article en page(s) : p.260-268 Langues : Anglais (eng) Mots-clés : Dopamine Serotonin Cortex Cocaine Prenatal Postnatal Index. décimale : PER Périodiques Résumé : The formation and function of the mammalian cerebral cortex relies on the complex interplay of a variety of genetic and environmental factors through protracted periods of gestational and postnatal development. Biogenic amine systems are important neuromodulators, both in the adult nervous system, and during critical epochs of brain development. Abnormalities in developmental programming likely contribute to developmental delays and multiple neurological and psychiatric disorders, often with symptom onset much later than the actual induction of pathology. We review several genetic and pharmacological models of dopamine, norepinephrine and serotonin modulation during development, each of which produces permanent changes in cerebral cortical structure and function. These models clearly illustrate the ability of these neurotransmitters to function beyond their classic roles and show their involvement in the development and modulation of fine brain circuitry that is sensitive to numerous effectors. Furthermore, these studies demonstrate the need to consider not only gene by environment interactions, but also gene by environment by developmental time interactions. En ligne : http://dx.doi.org/10.1007/s10803-008-0624-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=683 [article] Pleiotropic Effects of Neurotransmission during Development: Modulators of Modularity [texte imprimé] / Barbara L. THOMPSON, Auteur ; Gregg D. STANWOOD, Auteur . - 2009 . - p.260-268. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 39-2 (February 2009) . - p.260-268 Mots-clés : Dopamine Serotonin Cortex Cocaine Prenatal Postnatal Index. décimale : PER Périodiques Résumé : The formation and function of the mammalian cerebral cortex relies on the complex interplay of a variety of genetic and environmental factors through protracted periods of gestational and postnatal development. Biogenic amine systems are important neuromodulators, both in the adult nervous system, and during critical epochs of brain development. Abnormalities in developmental programming likely contribute to developmental delays and multiple neurological and psychiatric disorders, often with symptom onset much later than the actual induction of pathology. We review several genetic and pharmacological models of dopamine, norepinephrine and serotonin modulation during development, each of which produces permanent changes in cerebral cortical structure and function. These models clearly illustrate the ability of these neurotransmitters to function beyond their classic roles and show their involvement in the development and modulation of fine brain circuitry that is sensitive to numerous effectors. Furthermore, these studies demonstrate the need to consider not only gene by environment interactions, but also gene by environment by developmental time interactions. En ligne : http://dx.doi.org/10.1007/s10803-008-0624-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=683

The autism risk genes MET and PLAUR differentially impact cortical development / Kathie L. EAGLESON in Autism Research, 4-1 (February 2011)  

Public ISBD [article]  inAutism Research > 4-1 (February 2011) . - p.68-83 Titre : The autism risk genes MET and PLAUR differentially impact cortical development Type de document : texte imprimé Auteurs : Kathie L. EAGLESON, Auteur ; Daniel B. CAMPBELL, Auteur ; Barbara L. THOMPSON, Auteur ; Mica Y. BERGMAN, Auteur ; Pat LEVITT, Auteur Année de publication : 2011 Article en page(s) : p.68-83 Langues : Anglais (eng) Mots-clés : animal models  developmental neurobiology  neuroanatomy Index. décimale : PER Périodiques Résumé : Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Metfx/fx/ Dlx5/6cre mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Metfx/fx/ Dlx5/6cre mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements. En ligne : http://dx.doi.org/10.1002/aur.172 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=118 [article] The autism risk genes MET and PLAUR differentially impact cortical development [texte imprimé] / Kathie L. EAGLESON, Auteur ; Daniel B. CAMPBELL, Auteur ; Barbara L. THOMPSON, Auteur ; Mica Y. BERGMAN, Auteur ; Pat LEVITT, Auteur . - 2011 . - p.68-83. Langues : Anglais (eng) in Autism Research > 4-1 (February 2011) . - p.68-83 Mots-clés : animal models  developmental neurobiology  neuroanatomy Index. décimale : PER Périodiques Résumé : Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Metfx/fx/ Dlx5/6cre mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Metfx/fx/ Dlx5/6cre mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements. En ligne : http://dx.doi.org/10.1002/aur.172 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=118

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