title: Novel Primate Model of Serotonin Transporter Genetic Polymorphisms Associated with Gene Expression, Anxiety and Sensitivity to Antidepressants.
abstract: Genetic polymorphisms in the repeat upstream region of the serotonin transporter gene (SLC6A4) are associated with individual differences in stress reactivity, vulnerability to affective disorders, and response to pharmacotherapy. However, the molecular, neurodevelopmental and psychopharmacological mechanisms underlying the link between SLC6A4 polymorphisms and the emotionally vulnerable phenotype are not fully understood. Thus, using the marmoset monkey Callithrix jacchus we characterize here a new neurobiological model to help to address these questions. We first sequenced the marmoset SLC6A4 promoter and identified a double nucleotide polymorphism (-2053AC/CT) and two single-nucleotide polymorphisms (-2022C/T and -1592G/C) within the repeat upstream region. We showed their association with gene expression using in vivo quantitative PCR and with affective behavior using a primate test of anxiety (human intruder test). The low-expressing haplotype (AC/C/G) was linked with high anxiety while the high-expressing one (CT/T/C) was associated with an active coping strategy in response to threat. Pharmacological challenge with an acute dose of the selective serotonin reuptake inhibitor, citalopram, revealed a genotype-dependent behavioral response. While individuals homozygous for the high anxiety-related haplotype AC/C/G exhibited a dose-dependent, anxiogenic response, individuals homozygous for the low anxiety-related haplotype CT/T/C showed an opposing, dose-dependent anxiolytic effect. These findings provide a novel genetic and behavioral primate model to study the molecular, neurodevelopmental, and psychopharmacological mechanisms that underlie genetic variation-associated complex behaviors, with specific implications for the understanding of normal and abnormal serotonin actions and the development of personalized pharmacological treatments for psychiatric disorders.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Santangelo
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Yoshiro
authors.identifier: 0000-0002-4948-4646
authors.initials: Y
authors.lastname: Shiba
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Hannah F
authors.initials: HF
authors.lastname: Clarke
authors.affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Evelien Hs
authors.initials: EH
authors.lastname: Schut
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Cockcroft
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Roberts
mesh_terms: D000223:Adaptation, Psychological; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D001007:Anxiety / Q000235:genetics*; D001522:Behavior, Animal / Q000187:drug effects; D002144:Callithrix; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006239:Haplotypes; D008297:Male; D011110:Polymorphism, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors