Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory

Department of Psychology, New York University, New York, NY 10003, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2012; 109(14):5493-8. DOI: 10.1073/pnas.1202044109
Source: PubMed


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.

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    • "Previous studies have implied that the serotonin transporter expression seems to be a reliable neuronal marker related to memory mechanisms, its alterations and potential treatment [28]. In addition, it was reported that human serotonin transporter polyadenylation polymorphism can modulate the retention of fear extinction memory [29]. "
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    ABSTRACT: Caenorhabditis elegans is as an ideal model system for the study of mechanisms underlying learning and memory. In the present study, we employed C. elegans assay system of thermotaxis memory to investigate the possible role of serotonin neurotransmitter in memory control. Our data showed that both mutations of tph-1, bas-1, and cat-4 genes, required for serotonin synthesis, and mutations of mod-5 gene, encoding a serotonin reuptake transporter, resulted in deficits in thermotaxis memory behavior. Exogenous treatment with serotonin effectively recovered the deficits in thermotaxis memory of tph-1 and bas-1 mutants to the level of wild-type N2. Neuron-specific activity assay of TPH-1 suggests that serotonin might regulate the thermotaxis memory behavior by release from the ADF sensory neurons. Ablation of ADF sensory neurons by expressing a cell-death activator gene egl-1 decreased the thermotaxis memory, whereas activation of ADF neurons by expression of a constitutively active protein kinase C homologue (pkc-1(gf)) increased the thermotaxis memory and rescued the deficits in thermotaxis memory in tph-1 mutants. Moreover, serotonin released from the ADF sensory neurons might act through the G-protein-coupled serotonin receptors of SER-4 and SER-7 to regulate the thermotaxis memory behavior. Genetic analysis implies that serotonin might further target the insulin signaling pathway to regulate the thermotaxis memory behavior. Thus, our results suggest the possible crucial role of serotonin and ADF sensory neurons in thermotaxis memory control in C. elegans.
    PLoS ONE 11/2013; 8(11):e77779. DOI:10.1371/journal.pone.0077779 · 3.23 Impact Factor
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    • "For example, low LG and maternally separated offspring exhibit enhanced fear conditioning and impaired extinction (Champagne et al., 2008; Bagot et al., 2009; Callaghan and Richardson, 2011), whereas others associated brief maternal separation (15 min) with impaired fear extinction in spite of similar rates of initial conditioning (Wilber et al., 2007, 2009; Stevenson et al., 2009). Deficits in extinction have also been associated with the serotonin transporter in rodents (Wellman et al., 2007; Narayanan et al., 2011) and in people (Hartley et al., 2012), indicating that genetic risk for PTSD may be partly mediated by impaired fear extinction. A major challenge in applying extinction and reconsolidation as a long-term treatment is the relative transience of extinction relative to the original learning event and the requirement for pharmacological intervention for robust interference with reconsolidation (Pitman, 2011). "
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    ABSTRACT: Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by intrusive and persistent memories of a psychologically traumatic event that leads to significant functional and social impairment in affected individuals. The molecular bases underlying persistent outcomes of a transient traumatic event have remained elusive for many years, but recent studies in rodents have implicated epigenetic modifications of chromatin structure and DNA methylation as fundamental mechanisms for the induction and stabilization of fear memory. In addition to mediating adaptations to traumatic events that ultimately cause PTSD, epigenetic mechanisms are also involved in establishing individual differences in PTSD risk and resilience by mediating long-lasting effects of genes and early environment on adult function and behavior. In this review, we discuss the current evidence for epigenetic regulation of PTSD in human studies and in animal models and comment on ways in which these models can be expanded. In addition, we identify key outstanding questions in the study of epigenetic mechanisms of PTSD in the context of rapidly evolving technologies that are constantly updating and adjusting our understanding of epigenetic modifications and their functional roles. Finally, we discuss the potential application of epigenetic approaches in identifying markers of risk and resilience that can be utilized to promote early intervention and develop therapeutic strategies to combat PTSD after symptom onset.
    Frontiers in Psychiatry 06/2013; 4:60. DOI:10.3389/fpsyt.2013.00060
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    • "BDNF is not the only gene known to influence connectivity between the amygdala and other neural regions, however. In addition to the effects of BDNF on amygdala-PFC connectivity, polymorphisms in the catechol-O-methyltransferase (COMT) and serotonin transporter gene have been shown to modulate affective arousal and regulation as well as the retention of fear extinguished memories (Drabant et al., 2006; Hartley et al., 2012). While primarily studied within the context of affective disorders, it is clear to see how these findings also have important implications for future work in social neuroscience. "
    Frontiers in Human Neuroscience 02/2013; 7:20. DOI:10.3389/fnhum.2013.00020 · 2.99 Impact Factor
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