Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging / J. ELLEGOOD in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 24p. Titre : Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging Type de document : Texte imprimé et/ou numérique Auteurs : J. ELLEGOOD, Auteur ; Y. YEE, Auteur ; T. M. KERR, Auteur ; C. L. MULLER, Auteur ; R. D. BLAKELY, Auteur ; R. M. HENKELMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; J. P. LERCH, Auteur Article en page(s) : 24p. Langues : Anglais (eng) Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging [Texte imprimé et/ou numérique] / J. ELLEGOOD, Auteur ; Y. YEE, Auteur ; T. M. KERR, Auteur ; C. L. MULLER, Auteur ; R. D. BLAKELY, Auteur ; R. M. HENKELMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; J. P. LERCH, Auteur . - 24p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 24p. Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Choline transporter gene variation is associated with attention-deficit hyperactivity disorder / B. A. ENGLISH in Journal of Neurodevelopmental Disorders, 1-4 (December 2009)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 1-4 (December 2009) . - p.252-63 Titre : Choline transporter gene variation is associated with attention-deficit hyperactivity disorder Type de document : Texte imprimé et/ou numérique Auteurs : B. A. ENGLISH, Auteur ; M. K. HAHN, Auteur ; I. R. GIZER, Auteur ; M. MAZEI-ROBISON, Auteur ; A. STEELE, Auteur ; D. M. KURNIK, Auteur ; M. A. STEIN, Auteur ; Irwin D. WALDMAN, Auteur ; R. D. BLAKELY, Auteur Article en page(s) : p.252-63 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer's Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3' of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2-3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3'SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder. En ligne : http://dx.doi.org/10.1007/s11689-009-9033-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341 [article] Choline transporter gene variation is associated with attention-deficit hyperactivity disorder [Texte imprimé et/ou numérique] / B. A. ENGLISH, Auteur ; M. K. HAHN, Auteur ; I. R. GIZER, Auteur ; M. MAZEI-ROBISON, Auteur ; A. STEELE, Auteur ; D. M. KURNIK, Auteur ; M. A. STEIN, Auteur ; Irwin D. WALDMAN, Auteur ; R. D. BLAKELY, Auteur . - p.252-63. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 1-4 (December 2009) . - p.252-63 Index. décimale : PER Périodiques Résumé : The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer's Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3' of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2-3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3'SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder. En ligne : http://dx.doi.org/10.1007/s11689-009-9033-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341

Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model / H. DAI in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.38 Titre : Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model Type de document : Texte imprimé et/ou numérique Auteurs : H. DAI, Auteur ; Carrie R. JACKSON, Auteur ; G. L. DAVIS, Auteur ; R. D. BLAKELY, Auteur ; D. G. MCMAHON, Auteur Article en page(s) : p.38 Langues : Anglais (eng) Mots-clés : Ala559Val coding substitution  Anomalous dopamine efflux  Attention-deficit/hyperactivity disorder  Biomarker  Dopamine transporter  Electroretinogram Index. décimale : PER Périodiques Résumé : BACKGROUND: Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed. METHODS: Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice. RESULTS: Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D1 and D4 DA receptor agonists and suppressed in HOM mice by introducing D4 antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates. CONCLUSIONS: These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling. En ligne : http://dx.doi.org/10.1186/s11689-017-9215-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350 [article] Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model [Texte imprimé et/ou numérique] / H. DAI, Auteur ; Carrie R. JACKSON, Auteur ; G. L. DAVIS, Auteur ; R. D. BLAKELY, Auteur ; D. G. MCMAHON, Auteur . - p.38. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.38 Mots-clés : Ala559Val coding substitution  Anomalous dopamine efflux  Attention-deficit/hyperactivity disorder  Biomarker  Dopamine transporter  Electroretinogram Index. décimale : PER Périodiques Résumé : BACKGROUND: Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed. METHODS: Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice. RESULTS: Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D1 and D4 DA receptor agonists and suppressed in HOM mice by introducing D4 antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates. CONCLUSIONS: These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling. En ligne : http://dx.doi.org/10.1186/s11689-017-9215-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350

Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse / J. VEENSTRA-VANDERWEELE in Journal of Neurodevelopmental Disorders, 1-2 (June 2009)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 1-2 (June 2009) . - p.158-71 Titre : Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse Type de document : Texte imprimé et/ou numérique Auteurs : J. VEENSTRA-VANDERWEELE, Auteur ; T. N. JESSEN, Auteur ; B. J. THOMPSON, Auteur ; M. CARTER, Auteur ; H. C. PRASAD, Auteur ; J. A. STEINER, Auteur ; J. S. SUTCLIFFE, Auteur ; R. D. BLAKELY, Auteur Article en page(s) : p.158-71 Langues : Anglais (eng) Mots-clés : Autism  Polymorphism  Protein kinase G  Serotonin  Transgenic mouse  Transporter  p38 mitogen activated protein kinase Index. décimale : PER Périodiques Résumé : Alterations in peripheral and central indices of serotonin (5-hydroxytryptamine, 5-HT) production, storage and signaling have long been associated with autism. The 5-HT transporter gene (HTT, SERT, SLC6A4) has received considerable attention as a potential risk locus for autism-spectrum disorders, as well as disorders with overlapping symptoms, including obsessive-compulsive disorder (OCD). Here, we review our efforts to characterize rare, nonsynonymous polymorphisms in SERT derived from multiplex pedigrees carrying diagnoses of autism and OCD and present the initial stages of our effort to model one of these variants, Gly56Ala, in vivo. We generated a targeting vector to produce the Gly56Ala substitution in the Slc6a4 locus by homologous recombination. Following removal of a neomycin resistance selection cassette, animals exhibiting germline transmission of the Ala56 variant were bred to establish a breeding colony on a 129S6 background, suitable for initial evaluation of biochemical, physiological and behavioral alterations relative to SERT Gly56 (wild-type) animals. SERT Ala56 mice were achieved and exhibit a normal pattern of transmission. The initial growth and gross morphology of these animals is comparable to wildtype littermate controls. The SERT Ala56 variant can be propagated in 129S6 mice without apparent disruption of fertility and growth. We discuss both the opportunities and challenges that await the physiological/behavioral analysis of Gly56Ala transgenic mice, with particular reference to modeling autism-associated traits. En ligne : http://dx.doi.org/10.1007/s11689-009-9020-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341 [article] Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse [Texte imprimé et/ou numérique] / J. VEENSTRA-VANDERWEELE, Auteur ; T. N. JESSEN, Auteur ; B. J. THOMPSON, Auteur ; M. CARTER, Auteur ; H. C. PRASAD, Auteur ; J. A. STEINER, Auteur ; J. S. SUTCLIFFE, Auteur ; R. D. BLAKELY, Auteur . - p.158-71. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 1-2 (June 2009) . - p.158-71 Mots-clés : Autism  Polymorphism  Protein kinase G  Serotonin  Transgenic mouse  Transporter  p38 mitogen activated protein kinase Index. décimale : PER Périodiques Résumé : Alterations in peripheral and central indices of serotonin (5-hydroxytryptamine, 5-HT) production, storage and signaling have long been associated with autism. The 5-HT transporter gene (HTT, SERT, SLC6A4) has received considerable attention as a potential risk locus for autism-spectrum disorders, as well as disorders with overlapping symptoms, including obsessive-compulsive disorder (OCD). Here, we review our efforts to characterize rare, nonsynonymous polymorphisms in SERT derived from multiplex pedigrees carrying diagnoses of autism and OCD and present the initial stages of our effort to model one of these variants, Gly56Ala, in vivo. We generated a targeting vector to produce the Gly56Ala substitution in the Slc6a4 locus by homologous recombination. Following removal of a neomycin resistance selection cassette, animals exhibiting germline transmission of the Ala56 variant were bred to establish a breeding colony on a 129S6 background, suitable for initial evaluation of biochemical, physiological and behavioral alterations relative to SERT Gly56 (wild-type) animals. SERT Ala56 mice were achieved and exhibit a normal pattern of transmission. The initial growth and gross morphology of these animals is comparable to wildtype littermate controls. The SERT Ala56 variant can be propagated in 129S6 mice without apparent disruption of fertility and growth. We discuss both the opportunities and challenges that await the physiological/behavioral analysis of Gly56Ala transgenic mice, with particular reference to modeling autism-associated traits. En ligne : http://dx.doi.org/10.1007/s11689-009-9020-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341

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