Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory
- 19 March 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (14), 5493-5498
- https://doi.org/10.1073/pnas.1202044109
Abstract
Growing evidence suggests serotonin's role in anxiety and depression is mediated by its effects on learned fear associations. Pharmacological and genetic manipulations of serotonin signaling in mice alter the retention of fear extinction learning, which is inversely associated with anxious temperament in mice and humans. Here, we test whether genetic variation in serotonin signaling in the form of a common human serotonin transporter polyadenylation polymorphism (STPP/rs3813034) is associated with spontaneous fear recovery after extinction. We show that the risk allele of this polymorphism is associated with impaired retention of fear extinction memory and heightened anxiety and depressive symptoms. These STPP associations in humans mirror the phenotypic effects of serotonin transporter knockout in mice, highlighting the STPP as a potential genetic locus underlying interindividual differences in serotonin transporter function in humans. Furthermore, we show that the serotonin transporter polyadenylation profile associated with the STPP risk allele is altered through the chronic administration of fluoxetine, a treatment that also facilitates retention of extinction learning. The propensity to form persistent fear associations due to poor extinction recall may be an intermediate phenotype mediating the effects of genetic variation in serotonergic function on anxiety and depression. The consistency and specificity of these data across species provide robust support for this hypothesis and suggest that the little-studied STPP may be an important risk factor for mood and anxiety disorders in humans.Keywords
This publication has 53 references indexed in Scilit:
- Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic PhenotypesNeuropsychopharmacology, 2012
- Mechanisms and Consequences of Alternative PolyadenylationMolecular Cell, 2011
- Association of a Polyadenylation Polymorphism in the Serotonin Transporter and Panic DisorderBiological Psychiatry, 2010
- Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress DisorderBiological Psychiatry, 2009
- Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of DepressionJama-Journal Of The American Medical Association, 2009
- How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systemsNeuropharmacology, 2008
- Genetic variation in cortico-amygdala serotonin function and risk for stress-related diseaseNeuroscience & Biobehavioral Reviews, 2008
- Serotonin Transporter (5-HTTLPR) Genotype and Amygdala Activation: A Meta-AnalysisBiological Psychiatry, 2008
- The endophenotype concept in psychiatric geneticsPsychological Medicine, 2006
- Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey ReplicationArchives of General Psychiatry, 2005