Autism-relevant behaviors are minimally impacted by conditional deletion of Pten in oxytocinergic neurons / Amy E. CLIPPERTON-ALLEN in Autism Research, 9-12 (December 2016)  

Public ISBD [article]  inAutism Research > 9-12 (December 2016) . - p.1248-1262 Titre : Autism-relevant behaviors are minimally impacted by conditional deletion of Pten in oxytocinergic neurons Type de document : Texte imprimé et/ou numérique Auteurs : Amy E. CLIPPERTON-ALLEN, Auteur ; Youjun CHEN, Auteur ; Damon T. PAGE, Auteur Article en page(s) : p.1248-1262 Langues : Anglais (eng) Mots-clés : phosphatase and tensin homolog  autism spectrum disorder  oxytocin  social behavior  anxiety-like behavior  hypertrophy Index. décimale : PER Périodiques Résumé : Germline heterozygous mutations in Pten (phosphatase and tensin homolog) are associated with macrocephaly and autism spectrum disorders (ASD). Pten germline heterozygous (Pten+/?) mice approximate these mutations, and both sexes show widespread brain overgrowth and impaired social behavior. Strikingly similar behavior phenotypes have been reported in oxytocin (Oxt) and/or oxytocin receptor (OxtR) knockout mice. Thus, we hypothesized that the behavioral phenotypes of germline Pten+/? mice may be caused by reduced Pten function in Oxt-expressing cells. To investigate this, we tested mice in which Pten was conditionally deleted using oxytocin-Cre (Oxt-Cre+; PtenloxP/+, Oxt-Cre+; PtenloxP/loxP) on a battery including assays of social, repetitive, depression-like, and anxiety-like behaviors. Minimal behavioral abnormalities were found; decreased anxiety-like behavior in the open field test in Oxt-Cre+; PtenloxP/loxP males was the only result that phenocopied germline Pten+/? mice. However, Oxt cell size was dramatically increased in Oxt-Cre+; PtenloxP/loxP mice in adulthood. Thus, conditional deletion of Pten using Oxt-Cre has a profound effect on Oxt cell structure, but not on ASD-relevant behavior. We interpret these results as inconsistent with our starting hypothesis that reduced Pten function in Oxt-expressing cells causes the behavioral deficits observed in germline Pten+/? mice. En ligne : http://dx.doi.org/10.1002/aur.1641 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=298 [article] Autism-relevant behaviors are minimally impacted by conditional deletion of Pten in oxytocinergic neurons [Texte imprimé et/ou numérique] / Amy E. CLIPPERTON-ALLEN, Auteur ; Youjun CHEN, Auteur ; Damon T. PAGE, Auteur . - p.1248-1262. Langues : Anglais (eng) in Autism Research > 9-12 (December 2016) . - p.1248-1262 Mots-clés : phosphatase and tensin homolog  autism spectrum disorder  oxytocin  social behavior  anxiety-like behavior  hypertrophy Index. décimale : PER Périodiques Résumé : Germline heterozygous mutations in Pten (phosphatase and tensin homolog) are associated with macrocephaly and autism spectrum disorders (ASD). Pten germline heterozygous (Pten+/?) mice approximate these mutations, and both sexes show widespread brain overgrowth and impaired social behavior. Strikingly similar behavior phenotypes have been reported in oxytocin (Oxt) and/or oxytocin receptor (OxtR) knockout mice. Thus, we hypothesized that the behavioral phenotypes of germline Pten+/? mice may be caused by reduced Pten function in Oxt-expressing cells. To investigate this, we tested mice in which Pten was conditionally deleted using oxytocin-Cre (Oxt-Cre+; PtenloxP/+, Oxt-Cre+; PtenloxP/loxP) on a battery including assays of social, repetitive, depression-like, and anxiety-like behaviors. Minimal behavioral abnormalities were found; decreased anxiety-like behavior in the open field test in Oxt-Cre+; PtenloxP/loxP males was the only result that phenocopied germline Pten+/? mice. However, Oxt cell size was dramatically increased in Oxt-Cre+; PtenloxP/loxP mice in adulthood. Thus, conditional deletion of Pten using Oxt-Cre has a profound effect on Oxt cell structure, but not on ASD-relevant behavior. We interpret these results as inconsistent with our starting hypothesis that reduced Pten function in Oxt-expressing cells causes the behavioral deficits observed in germline Pten+/? mice. En ligne : http://dx.doi.org/10.1002/aur.1641 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=298

Genetic Suppression of mTOR Rescues Synaptic and Social Behavioral Abnormalities in a Mouse Model of Pten Haploinsufficiency / W. C. HUANG in Autism Research, 12-10 (October 2019)  

Public ISBD [article]  inAutism Research > 12-10 (October 2019) . - p.1463-1471 Titre : Genetic Suppression of mTOR Rescues Synaptic and Social Behavioral Abnormalities in a Mouse Model of Pten Haploinsufficiency Type de document : Texte imprimé et/ou numérique Auteurs : W. C. HUANG, Auteur ; Y. CHEN, Auteur ; Damon T. PAGE, Auteur Article en page(s) : p.1463-1471 Langues : Anglais (eng) Mots-clés : Pten  macrocephaly  network activity  social behavior  synapses Index. décimale : PER Périodiques Résumé : Heterozygous mutations in PTEN, which encodes a negative regulator of the mTOR and beta-catenin signaling pathways, cause macrocephaly/autism syndrome. However, the neurobiological substrates of the core symptoms of this syndrome are poorly understood. Here, we investigate the relationship between cerebral cortical overgrowth and social behavior deficits in conditional Pten heterozygous female mice (Pten cHet) using Emx1-Cre, which is expressed in cortical pyramidal neurons and a subset of glia. We found that conditional heterozygous mutation of Ctnnb1 (encoding beta-catenin) suppresses Pten cHet cortical overgrowth, but not social behavioral deficits, whereas conditional heterozygous mutation of Mtor suppresses social behavioral deficits, but not cortical overgrowth. Neuronal activity in response to social cues and excitatory synapse markers are elevated in the medial prefrontal cortex (mPFC) of Pten cHet mice, and heterozygous mutation in Mtor, but not Ctnnb1, rescues these phenotypes. These findings indicate that macroscale cerebral cortical overgrowth and social behavioral phenotypes caused by Pten haploinsufficiency can be dissociated based on responsiveness to genetic suppression of Ctnnb1 or Mtor. Furthermore, neuronal connectivity appears to be one potential substrate for mTOR-mediated suppression of social behavioral deficits in Pten haploinsufficient mice. Autism Res 2019, 12: 1463-1471. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A subgroup of individuals with autism display overgrowth of the head and the brain during development. Using a mouse model of an autism risk gene, Pten, that displays both brain overgrowth and social behavioral deficits, we show here that that these two symptoms can be dissociated. Reversal of social behavioral deficits in this model is associated with rescue of abnormal synaptic markers and neuronal activity. En ligne : http://dx.doi.org/10.1002/aur.2186 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408 [article] Genetic Suppression of mTOR Rescues Synaptic and Social Behavioral Abnormalities in a Mouse Model of Pten Haploinsufficiency [Texte imprimé et/ou numérique] / W. C. HUANG, Auteur ; Y. CHEN, Auteur ; Damon T. PAGE, Auteur . - p.1463-1471. Langues : Anglais (eng) in Autism Research > 12-10 (October 2019) . - p.1463-1471 Mots-clés : Pten  macrocephaly  network activity  social behavior  synapses Index. décimale : PER Périodiques Résumé : Heterozygous mutations in PTEN, which encodes a negative regulator of the mTOR and beta-catenin signaling pathways, cause macrocephaly/autism syndrome. However, the neurobiological substrates of the core symptoms of this syndrome are poorly understood. Here, we investigate the relationship between cerebral cortical overgrowth and social behavior deficits in conditional Pten heterozygous female mice (Pten cHet) using Emx1-Cre, which is expressed in cortical pyramidal neurons and a subset of glia. We found that conditional heterozygous mutation of Ctnnb1 (encoding beta-catenin) suppresses Pten cHet cortical overgrowth, but not social behavioral deficits, whereas conditional heterozygous mutation of Mtor suppresses social behavioral deficits, but not cortical overgrowth. Neuronal activity in response to social cues and excitatory synapse markers are elevated in the medial prefrontal cortex (mPFC) of Pten cHet mice, and heterozygous mutation in Mtor, but not Ctnnb1, rescues these phenotypes. These findings indicate that macroscale cerebral cortical overgrowth and social behavioral phenotypes caused by Pten haploinsufficiency can be dissociated based on responsiveness to genetic suppression of Ctnnb1 or Mtor. Furthermore, neuronal connectivity appears to be one potential substrate for mTOR-mediated suppression of social behavioral deficits in Pten haploinsufficient mice. Autism Res 2019, 12: 1463-1471. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A subgroup of individuals with autism display overgrowth of the head and the brain during development. Using a mouse model of an autism risk gene, Pten, that displays both brain overgrowth and social behavioral deficits, we show here that that these two symptoms can be dissociated. Reversal of social behavioral deficits in this model is associated with rescue of abnormal synaptic markers and neuronal activity. En ligne : http://dx.doi.org/10.1002/aur.2186 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408

Reduced conditioned fear response in mice that lack Dlx1 and show subtype-specific loss of interneurons / R. MAO in Journal of Neurodevelopmental Disorders, 1-3 (September 2009)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 1-3 (September 2009) . - p.224-36 Titre : Reduced conditioned fear response in mice that lack Dlx1 and show subtype-specific loss of interneurons Type de document : Texte imprimé et/ou numérique Auteurs : R. MAO, Auteur ; Damon T. PAGE, Auteur ; I. MERZLYAK, Auteur ; C. KIM, Auteur ; L. H. TECOTT, Auteur ; P. H. JANAK, Auteur ; J. L. RUBENSTEIN, Auteur ; M. SUR, Auteur Article en page(s) : p.224-36 Langues : Anglais (eng) Mots-clés : Associative learning  Behavior  Calretinin  Fear conditioning  GABAergic  Hyperactivity  Inhibitory  Interneuron  Neuropsychiatric disease  Prepulse inhibition Index. décimale : PER Périodiques Résumé : UNLABELLED: The inhibitory GABAergic system has been implicated in multiple neuropsychiatric diseases such as schizophrenia and autism. The Dlx homeobox transcription factor family is essential for development and function of GABAergic interneurons. Mice lacking the Dlx1 gene have postnatal subtype-specific loss of interneurons and reduced IPSCs in their cortex and hippocampus. To ascertain consequences of these changes in the GABAergic system, we performed a battery of behavioral assays on the Dlx1 mutant mice, including zero maze, open field, locomotor activity, food intake, rotarod, tail suspension, fear conditioning assays (context and trace), prepulse inhibition, and working memory related tasks (spontaneous alteration task and spatial working memory task). Dlx1 mutant mice displayed elevated activity levels in open field, locomotor activity, and tail suspension tests. These mice also showed deficits in contextual and trace fear conditioning, and possibly in prepulse inhibition. Their learning deficits were not global, as the mutant mice did not differ from the wild-type controls in tests of working memory. Our findings demonstrate a critical role for the Dlx1 gene, and likely the subclasses of interneurons that are affected by the lack of this gene, in behavioral inhibition and associative fear learning. These observations support the involvement of particular components of the GABAergic system in specific behavioral phenotypes related to complex neuropsychiatric diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-009-9025-8) contains supplementary material, which is available to authorized users. En ligne : http://dx.doi.org/10.1007/s11689-009-9025-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341 [article] Reduced conditioned fear response in mice that lack Dlx1 and show subtype-specific loss of interneurons [Texte imprimé et/ou numérique] / R. MAO, Auteur ; Damon T. PAGE, Auteur ; I. MERZLYAK, Auteur ; C. KIM, Auteur ; L. H. TECOTT, Auteur ; P. H. JANAK, Auteur ; J. L. RUBENSTEIN, Auteur ; M. SUR, Auteur . - p.224-36. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 1-3 (September 2009) . - p.224-36 Mots-clés : Associative learning  Behavior  Calretinin  Fear conditioning  GABAergic  Hyperactivity  Inhibitory  Interneuron  Neuropsychiatric disease  Prepulse inhibition Index. décimale : PER Périodiques Résumé : UNLABELLED: The inhibitory GABAergic system has been implicated in multiple neuropsychiatric diseases such as schizophrenia and autism. The Dlx homeobox transcription factor family is essential for development and function of GABAergic interneurons. Mice lacking the Dlx1 gene have postnatal subtype-specific loss of interneurons and reduced IPSCs in their cortex and hippocampus. To ascertain consequences of these changes in the GABAergic system, we performed a battery of behavioral assays on the Dlx1 mutant mice, including zero maze, open field, locomotor activity, food intake, rotarod, tail suspension, fear conditioning assays (context and trace), prepulse inhibition, and working memory related tasks (spontaneous alteration task and spatial working memory task). Dlx1 mutant mice displayed elevated activity levels in open field, locomotor activity, and tail suspension tests. These mice also showed deficits in contextual and trace fear conditioning, and possibly in prepulse inhibition. Their learning deficits were not global, as the mutant mice did not differ from the wild-type controls in tests of working memory. Our findings demonstrate a critical role for the Dlx1 gene, and likely the subclasses of interneurons that are affected by the lack of this gene, in behavioral inhibition and associative fear learning. These observations support the involvement of particular components of the GABAergic system in specific behavioral phenotypes related to complex neuropsychiatric diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-009-9025-8) contains supplementary material, which is available to authorized users. En ligne : http://dx.doi.org/10.1007/s11689-009-9025-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341

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