Basal ganglia and autism – a translational perspective / Krishna SUBRAMANIAN in Autism Research, 10-11 (November 2017)  

Public ISBD [article]  inAutism Research > 10-11 (November 2017) . - p.1751-1775 Titre : Basal ganglia and autism – a translational perspective Type de document : Texte imprimé et/ou numérique Auteurs : Krishna SUBRAMANIAN, Auteur ; Cheryl BRANDENBURG, Auteur ; Fernanda ORSATI, Auteur ; Jean-Jacques SOGHOMONIAN, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur Article en page(s) : p.1751-1775 Langues : Anglais (eng) Mots-clés : basal ganglia  animal models  motor, autism  neuroanatomy  neuroimaging  neuropathology Index. décimale : PER Périodiques Résumé : The basal ganglia are a collection of nuclei below the cortical surface that are involved in both motor and non-motor functions, including higher order cognition, social interactions, speech, and repetitive behaviors. Motor development milestones that are delayed in autism such as gross motor, fine motor and walking can aid in early diagnosis of autism. Neuropathology and neuroimaging findings in autism cases revealed volumetric changes and altered cell density in select basal ganglia nuclei. Interestingly, in autism, both the basal ganglia and the cerebellum are impacted both in their motor and non-motor domains and recently, found to be connected via the pons through a short disynaptic pathway. In typically developing individuals, the basal ganglia plays an important role in: eye movement, movement coordination, sensory modulation and processing, eye-hand coordination, action chaining, and inhibition control. Genetic models have proved to be useful toward understanding cellular and molecular changes at the synaptic level in the basal ganglia that may in part contribute to these autism-related behaviors. In autism, basal ganglia functions in motor skill acquisition and development are altered, thus disrupting the normal flow of feedback to the cortex. Taken together, there is an abundance of emerging evidence that the basal ganglia likely plays critical roles in maintaining an inhibitory balance between cortical and subcortical structures, critical for normal motor actions and cognitive functions. In autism, this inhibitory balance is disturbed thus impacting key pathways that affect normal cortical network activity. Autism Res 2017, 10: 1751–1775. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor and cognitive functions in the autism brain. En ligne : http://dx.doi.org/10.1002/aur.1837 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=322 [article] Basal ganglia and autism – a translational perspective [Texte imprimé et/ou numérique] / Krishna SUBRAMANIAN, Auteur ; Cheryl BRANDENBURG, Auteur ; Fernanda ORSATI, Auteur ; Jean-Jacques SOGHOMONIAN, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur . - p.1751-1775. Langues : Anglais (eng) in Autism Research > 10-11 (November 2017) . - p.1751-1775 Mots-clés : basal ganglia  animal models  motor, autism  neuroanatomy  neuroimaging  neuropathology Index. décimale : PER Périodiques Résumé : The basal ganglia are a collection of nuclei below the cortical surface that are involved in both motor and non-motor functions, including higher order cognition, social interactions, speech, and repetitive behaviors. Motor development milestones that are delayed in autism such as gross motor, fine motor and walking can aid in early diagnosis of autism. Neuropathology and neuroimaging findings in autism cases revealed volumetric changes and altered cell density in select basal ganglia nuclei. Interestingly, in autism, both the basal ganglia and the cerebellum are impacted both in their motor and non-motor domains and recently, found to be connected via the pons through a short disynaptic pathway. In typically developing individuals, the basal ganglia plays an important role in: eye movement, movement coordination, sensory modulation and processing, eye-hand coordination, action chaining, and inhibition control. Genetic models have proved to be useful toward understanding cellular and molecular changes at the synaptic level in the basal ganglia that may in part contribute to these autism-related behaviors. In autism, basal ganglia functions in motor skill acquisition and development are altered, thus disrupting the normal flow of feedback to the cortex. Taken together, there is an abundance of emerging evidence that the basal ganglia likely plays critical roles in maintaining an inhibitory balance between cortical and subcortical structures, critical for normal motor actions and cognitive functions. In autism, this inhibitory balance is disturbed thus impacting key pathways that affect normal cortical network activity. Autism Res 2017, 10: 1751–1775. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor and cognitive functions in the autism brain. En ligne : http://dx.doi.org/10.1002/aur.1837 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=322

Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies / Andre W. PHILLIPS ; Elena ARTIMOVICH ; Jonathan E. NESTOR ; John P. HUSSMAN ; Gene J. BLATT in Autism Research, 9-5 (May 2016)  

Public ISBD [article]  inAutism Research > 9-5 (May 2016) . - p.513-535 Titre : Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies Type de document : Texte imprimé et/ou numérique Auteurs : Andre W. PHILLIPS, Auteur ; Elena ARTIMOVICH, Auteur ; Jonathan E. NESTOR, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur Article en page(s) : p.513-535 Langues : Anglais (eng) Mots-clés : human stem cells  autism  drug-screening  high-throughput  inducible pluripotent stem cells  CRISPR  optogenetics  organoids Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1570 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=289 [article] Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies [Texte imprimé et/ou numérique] / Andre W. PHILLIPS, Auteur ; Elena ARTIMOVICH, Auteur ; Jonathan E. NESTOR, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur . - p.513-535. Langues : Anglais (eng) in Autism Research > 9-5 (May 2016) . - p.513-535 Mots-clés : human stem cells  autism  drug-screening  high-throughput  inducible pluripotent stem cells  CRISPR  optogenetics  organoids Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1570 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=289

A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism / John P. HUSSMAN in Molecular Autism, (January 2011)  

Public ISBD [article]  inMolecular Autism > (January 2011) . - 16 p. Titre : A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism Type de document : Texte imprimé et/ou numérique Auteurs : John P. HUSSMAN, Auteur ; Ren-Hua CHUNG, Auteur ; Anthony J. GRISWOLD, Auteur ; James M. JAWORSKI, Auteur ; Daria SALYAKINA, Auteur ; Deqiong MA, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Jeffery M. VANCE, Auteur ; Eden R. MARTIN, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur Année de publication : 2011 Article en page(s) : 16 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. Methods GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology. Results Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets. Conclusions As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism. En ligne : http://dx.doi.org/10.1186/2040-2392-2-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=121 [article] A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism [Texte imprimé et/ou numérique] / John P. HUSSMAN, Auteur ; Ren-Hua CHUNG, Auteur ; Anthony J. GRISWOLD, Auteur ; James M. JAWORSKI, Auteur ; Daria SALYAKINA, Auteur ; Deqiong MA, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Jeffery M. VANCE, Auteur ; Eden R. MARTIN, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur . - 2011 . - 16 p. Langues : Anglais (eng) in Molecular Autism > (January 2011) . - 16 p. Index. décimale : PER Périodiques Résumé : Background Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. Methods GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology. Results Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets. Conclusions As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism. En ligne : http://dx.doi.org/10.1186/2040-2392-2-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=121

Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants / Anthony J. GRISWOLD in Molecular Autism, (July 2015)  

Public ISBD [article]  inMolecular Autism > (July 2015) . - p.1-11 Titre : Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants Type de document : Texte imprimé et/ou numérique Auteurs : Anthony J. GRISWOLD, Auteur ; Nicole D. DUEKER, Auteur ; Derek BOOVEN, Auteur ; Joseph A. RANTUS, Auteur ; James M. JAWORSKI, Auteur ; Susan H. SLIFER, Auteur ; Michael A. SCHMIDT, Auteur ; William HULME, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Michael L. CUCCARO, Auteur ; Eden R. MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; John P. HUSSMAN, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur Article en page(s) : p.1-11 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. En ligne : http://dx.doi.org/10.1186/s13229-015-0034-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants [Texte imprimé et/ou numérique] / Anthony J. GRISWOLD, Auteur ; Nicole D. DUEKER, Auteur ; Derek BOOVEN, Auteur ; Joseph A. RANTUS, Auteur ; James M. JAWORSKI, Auteur ; Susan H. SLIFER, Auteur ; Michael A. SCHMIDT, Auteur ; William HULME, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Michael L. CUCCARO, Auteur ; Eden R. MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; John P. HUSSMAN, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur . - p.1-11. Langues : Anglais (eng) in Molecular Autism > (July 2015) . - p.1-11 Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. En ligne : http://dx.doi.org/10.1186/s13229-015-0034-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

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