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FKBP5 polymorphisms influence pre-learning stress-induced alterations of learning and memory.

ABSTRACT: FK506 binding protein 51 (FKBP5) is a co-chaperone of heat shock protein 90 and significantly influences glucocorticoid receptor sensitivity. Single nucleotide polymorphisms (SNPs) in the FKBP5 gene are associated with altered hypothalamus-pituitary-adrenal (HPA) axis function, changes in the structure and function of several cognitive brain areas, and increased susceptibility to post-traumatic stress disorder, major depression, bipolar disorder and suicidal events. The mechanisms underlying these associations are largely unknown, but it has been speculated that the influence of these SNPs on emotional memory systems may play a role. In the present study, 112 participants were exposed to the socially evaluated cold pressor test (stress) or control (no stress) conditions immediately prior to learning a list of 42 words. Participant memory was assessed immediately after learning (free recall) and 24 h later (free recall and recognition). Participants provided a saliva sample that enabled the genotyping of three FKBP5 polymorphisms: rs1360780, rs3800373 and rs9296158. Results showed that stress impaired immediate recall in risk allele carriers. More importantly, stress enhanced long-term recall and recognition memory in non-carriers of the risk alleles, effects that were completely absent in risk allele carriers. Follow-up analyses revealed that memory performance was correlated with salivary cortisol levels in non-carriers, but not in carriers. These findings suggest that FKBP5 risk allele carriers may possess a sensitized stress response system, perhaps specifically for stress-induced changes in corticosteroid levels, which might aid our understanding of how SNPs in the FKBP5 gene confer increased risk for stress-related psychological disorders and their related phenotypes.

SUBMITTER: Zoladz PR

PROVIDER: S-EPMC5339029 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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FKBP5 polymorphisms influence pre-learning stress-induced alterations of learning and memory.

Zoladz Phillip R PR Dailey Alison M AM Nagle Hannah E HE Fiely Miranda K MK Mosley Brianne E BE Brown Callie M CM Duffy Tessa J TJ Scharf Amanda R AR Earley McKenna B MB Rorabaugh Boyd R BR

The European journal of neuroscience 20170215 5

FK506 binding protein 51 (FKBP5) is a co-chaperone of heat shock protein 90 and significantly influences glucocorticoid receptor sensitivity. Single nucleotide polymorphisms (SNPs) in the FKBP5 gene are associated with altered hypothalamus-pituitary-adrenal (HPA) axis function, changes in the structure and function of several cognitive brain areas, and increased susceptibility to post-traumatic stress disorder, major depression, bipolar disorder and suicidal events. The mechanisms underlying the ...[more]

PMID: 28002634

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Project description:Stress is a fundamental biological response that can be associated with alterations in cognitive processes. Unhealthy dietary habits are proposed to modulate this effect, notably through their pro-inflammatory potential. This cross-sectional study aimed to evaluate the influence of an obesogenic dietary pattern with inflammatory potential on stress-induced cognitive alterations in healthy volunteers. Fifty healthy adult participants were stratified into two diet groups: obesogenic vs. non-obesogenic, based on their self-reported consumption of fat, sugar, and salt, assessed by the French National Program for Nutrition and Health questionnaire and a food frequency questionnaire. Serum high-sensitive C-reactive protein (hsCRP) was measured as a marker of systemic inflammation using ELISA. Verbal memory and sustained attention were evaluated through the Verbal Recognition Memory (VRM) test and the Rapid Visual Information Processing (RVP) test respectively, from the Cambridge Neuropsychological Test Automated Battery. Assessments were performed before and after exposure to the psychological stressor Trier Social Stress Test (TSST). Stress response was evaluated by subjective stress perception, salivary cortisol, blood pressure, and heart rate. Twenty-two participants (44%) presented an obesogenic diet. Systemic inflammation was significantly higher in the obesogenic diet group (p=0.005). The TSST induced a significant stress response, regardless of dietary habits (Time effect p < 0.001). In the whole sample, exposure to TSST was associated with cognitive changes in the form of impaired performance on the VRM test and overall improved RVP scores. However, the obesogenic diet group exhibited an increased total number of false alarms (Time x Diet: p=0.014) on the RVP test after TSST exposure as well as a greater impairment in immediate verbal recognition on the VRM test (Time x Diet: p=0.002). This effect was not associated with the inflammatory component of the obesogenic diet. These results suggest that an obesogenic diet may sensitize healthy individuals to the detrimental effects of acute stress on cognitive performance.

Project description:ContextIn addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability.ObjectiveTo increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene x environment interactions of child abuse, level of non-child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5.Design, setting, and participantsA cross-sectional study examining genetic and psychological risk factors in 900 nonpsychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non-child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007.Main outcome measuresSeverity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non-child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus.ResultsLevel of child abuse and non-child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs > or =2 types of abuse, 20.93 [14.32]; and for no non-child abuse trauma, 3.58 [6.27] vs > or =4 types, 16.74 [12.90]; P < .001). Although FKBP5 SNPs did not directly predict PTSD symptom outcome or interact with level of non-child abuse trauma to predict PTSD symptom severity, 4 SNPs in the FKBP5 locus significantly interacted (rs9296158, rs3800373, rs1360780, and rs9470080; minimum P = .0004) with the severity of child abuse to predict level of adult PTSD symptoms after correcting for multiple testing. This gene x environment interaction remained significant when controlling for depression severity scores, age, sex, levels of non-child abuse trauma exposure, and genetic ancestry. This genetic interaction was also paralleled by FKBP5 genotype-dependent and PTSD-dependent effects on glucocorticoid receptor sensitivity, measured by the dexamethasone suppression test.ConclusionsFour SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non-child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.

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FKBP5 polymorphisms influence pre-learning stress-induced alterations of learning and memory.

Publications

FKBP5 polymorphisms influence pre-learning stress-induced alterations of learning and memory.

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