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Auteur Mathew PLETCHER |
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Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis / Diane T. STEPHENSON in Molecular Autism, (May 2011)
[article]
Titre : Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis Type de document : Texte imprimé et/ou numérique Auteurs : Diane T. STEPHENSON, Auteur ; Sharon M. O'NEILL, Auteur ; Sapna NARAYAN, Auteur ; Aadhya TIWARI, Auteur ; Elizabeth ARNOLD, Auteur ; Harry SAMAROO, Auteur ; Fu DU, Auteur ; Robert RING, Auteur ; Brian M. CAMPBELL, Auteur ; Mathew PLETCHER, Auteur ; Vidita A. VAIDYA, Auteur ; Daniel MORTON, Auteur Année de publication : 2011 Article en page(s) : 76 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background
The inbred mouse strain, BTBR T+ tf/J (BTBR) exhibits behavioral deficits which mimic the core deficits of autism. Neuroanatomically, the BTBR strain is also characterized by a complete absence of the corpus callosum. The goal of this study was to identify novel molecular and cellular changes in the BTBR mouse focusing on, neuronal, synaptic, glial and plasticity markers in the limbic system as a model for identifying putative molecular and cellular substrates associated with autistic behaviors. .
Methods
Forebrains of 8 to 10 week old male BTBR and aged matched C57Bl/6J controls were evaluated by immunohistochemistry using free floating and paraffin embedded sections. Twenty antibodies directed to antigens specific to neurons, synapses and glia were used. Nissl, Timm's and acetylcholinesterase (AchE) stains were performed to assess cytoarchitecture, mossy fibers and cholinergic fiber density, respectively. In the hippocampus, quantitative stereological estimates for the mitotic marker bromodeoxyuridine were performed to determine hippocampal progenitor proliferation, survival and differentiation and BDNF mRNA was quantified by in situ hybridization. Quantitative image analysis was performed for NG2, doublecortin, NeuroD, GAD67 and PSA-NCAM.
Results
In midline structures including the region of the absent corpus callosum of BTBR mice, myelin markers myelin basic protein (MBP) and 2' , 3' -cyclic nucleotide 3' -phosphodiesterase (CNPase) were reduced and oligodendrocyte precursor NG2 was increased. MBP and CNPase were expressed in small ectopic white matter bundles within the cingulate cortex. Microglia and astrocytes showed no evidence of gliosis, yet orientations of glial fibers were altered in specific white matter areas. In the hippocampus, evidence of reduced neurogenesis included significant reductions in the number of doublecortin, PSA-NCAM, and NeuroD immunoreactive cells in the subgranular zone of the dentate gyrus and a marked reduction in the number of BrdU positive progenitors Furthermore, a significant and profound reduction in BDNF mRNA in the BTBR dentate gyrus was observed. No significant differences were observed in the expression of acetylcholinesterase, mossy fiber synapses, and immunoreactivities for MAP2, parvalbumin, GAD65 and GAD67.
Conclusions
We documented modest and selective alterations in glia, neurons and synapses in BTBR forebrain, along with reduced adult hippocampal neurogenesis. Of all markers examined, the most distinctive changes were observed in the neurodevelopmental proteins NG2, PSA-NCAM, NeuroD and doublecortin. Our results are consistent with aberrant development of the nervous system in BTBR mice and may reveal novel substrates to link callosal abnormalities and autistic behaviors. The changes that we observed in the BTBR mice suggest potential novel therapeutic strategies for intervention in autism spectrum disorders.En ligne : http://dx.doi.org/10.1186/2040-2392-2-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=131
in Molecular Autism > (May 2011) . - 76 p.[article] Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis [Texte imprimé et/ou numérique] / Diane T. STEPHENSON, Auteur ; Sharon M. O'NEILL, Auteur ; Sapna NARAYAN, Auteur ; Aadhya TIWARI, Auteur ; Elizabeth ARNOLD, Auteur ; Harry SAMAROO, Auteur ; Fu DU, Auteur ; Robert RING, Auteur ; Brian M. CAMPBELL, Auteur ; Mathew PLETCHER, Auteur ; Vidita A. VAIDYA, Auteur ; Daniel MORTON, Auteur . - 2011 . - 76 p.
Langues : Anglais (eng)
in Molecular Autism > (May 2011) . - 76 p.
Index. décimale : PER Périodiques Résumé : Background
The inbred mouse strain, BTBR T+ tf/J (BTBR) exhibits behavioral deficits which mimic the core deficits of autism. Neuroanatomically, the BTBR strain is also characterized by a complete absence of the corpus callosum. The goal of this study was to identify novel molecular and cellular changes in the BTBR mouse focusing on, neuronal, synaptic, glial and plasticity markers in the limbic system as a model for identifying putative molecular and cellular substrates associated with autistic behaviors. .
Methods
Forebrains of 8 to 10 week old male BTBR and aged matched C57Bl/6J controls were evaluated by immunohistochemistry using free floating and paraffin embedded sections. Twenty antibodies directed to antigens specific to neurons, synapses and glia were used. Nissl, Timm's and acetylcholinesterase (AchE) stains were performed to assess cytoarchitecture, mossy fibers and cholinergic fiber density, respectively. In the hippocampus, quantitative stereological estimates for the mitotic marker bromodeoxyuridine were performed to determine hippocampal progenitor proliferation, survival and differentiation and BDNF mRNA was quantified by in situ hybridization. Quantitative image analysis was performed for NG2, doublecortin, NeuroD, GAD67 and PSA-NCAM.
Results
In midline structures including the region of the absent corpus callosum of BTBR mice, myelin markers myelin basic protein (MBP) and 2' , 3' -cyclic nucleotide 3' -phosphodiesterase (CNPase) were reduced and oligodendrocyte precursor NG2 was increased. MBP and CNPase were expressed in small ectopic white matter bundles within the cingulate cortex. Microglia and astrocytes showed no evidence of gliosis, yet orientations of glial fibers were altered in specific white matter areas. In the hippocampus, evidence of reduced neurogenesis included significant reductions in the number of doublecortin, PSA-NCAM, and NeuroD immunoreactive cells in the subgranular zone of the dentate gyrus and a marked reduction in the number of BrdU positive progenitors Furthermore, a significant and profound reduction in BDNF mRNA in the BTBR dentate gyrus was observed. No significant differences were observed in the expression of acetylcholinesterase, mossy fiber synapses, and immunoreactivities for MAP2, parvalbumin, GAD65 and GAD67.
Conclusions
We documented modest and selective alterations in glia, neurons and synapses in BTBR forebrain, along with reduced adult hippocampal neurogenesis. Of all markers examined, the most distinctive changes were observed in the neurodevelopmental proteins NG2, PSA-NCAM, NeuroD and doublecortin. Our results are consistent with aberrant development of the nervous system in BTBR mice and may reveal novel substrates to link callosal abnormalities and autistic behaviors. The changes that we observed in the BTBR mice suggest potential novel therapeutic strategies for intervention in autism spectrum disorders.En ligne : http://dx.doi.org/10.1186/2040-2392-2-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=131 Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action / Thomas LANZ in Molecular Autism, (November 2013)
[article]
Titre : Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action Type de document : Texte imprimé et/ou numérique Auteurs : Thomas LANZ, Auteur ; Edward GUILMETTE, Auteur ; Mark GOSINK, Auteur ; James FISCHER, Auteur ; Lawrence FITZGERALD, Auteur ; Diane STEPHENSON, Auteur ; Mathew PLETCHER, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Austism spectrum disorder (ASD) is a heterogeneous behavioral disorder or condition characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a core clinical disability. Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA constructs. Whole genome expression analysis was conducted for each of the knockdown cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing an anti-luciferase shRNA. Gene set enrichment and a causal reasoning engine was employed to identify pathway level perturbations generated by the transcript knockdown. Quantification of the shRNA targets confirmed the successful knockdown at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients. En ligne : http://dx.doi.org/10.1186/2040-2392-4-45 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227
in Molecular Autism > (November 2013)[article] Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action [Texte imprimé et/ou numérique] / Thomas LANZ, Auteur ; Edward GUILMETTE, Auteur ; Mark GOSINK, Auteur ; James FISCHER, Auteur ; Lawrence FITZGERALD, Auteur ; Diane STEPHENSON, Auteur ; Mathew PLETCHER, Auteur.
Langues : Anglais (eng)
in Molecular Autism > (November 2013)
Index. décimale : PER Périodiques Résumé : Austism spectrum disorder (ASD) is a heterogeneous behavioral disorder or condition characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a core clinical disability. Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA constructs. Whole genome expression analysis was conducted for each of the knockdown cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing an anti-luciferase shRNA. Gene set enrichment and a causal reasoning engine was employed to identify pathway level perturbations generated by the transcript knockdown. Quantification of the shRNA targets confirmed the successful knockdown at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients. En ligne : http://dx.doi.org/10.1186/2040-2392-4-45 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227