Serotonin transporter polyadenylation polymorphism modulates the retention of fear extension 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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    • "specifically, facilitates extinction (Bowers and Ressler, 2015; Gunduz-Cinar et al, 2013b; Micale et al, 2013). In parallel to this work on eCBs, a number of recent studies have demonstrated that chronic treatment with fluoxetine, but not certain other SSRIs, such as citalopram (Burghardt and Bauer, 2013), facilitates extinction (Camp et al, 2012; Deschaux et al, 2011, 2013; Hartley et al, 2012; Karpova et al, 2012; Norcross et al, 2008; Popova et al, 2014; Riddle et al, 2013; Spennato et al, 2008). Conversely, acute fluoxetine administration increases conditioned fear in rodents; reminiscent of the heighted anxiety experienced by some patients during the early stages of SSRI treatment (Burghardt et al, 2007). "
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    ABSTRACT: Pharmacologically elevating brain endocannabinoids (eCBs) shares anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's pro-extinction effects, we integrated biochemical, electrophysiological, pharmacological and behavioral techniques, employing the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase (FAAH). Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1Rs. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the pro-extinction effects of a major pharmacotherapy for Trauma- and Stressor-related Disorders and Anxiety Disorders.Neuropsychopharmacology accepted article preview online, 30 October 2015. doi:10.1038/npp.2015.318.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2015; DOI:10.1038/npp.2015.318 · 7.05 Impact Factor
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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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