Pharmacological Modulation of the Psychiatric Risk Factor FKBP51 Alters Efficiency of Common Antidepressant Drugs

Despite a growing body of research over the last few decades, mental disorders, including anxiety disorders or depression, are still one of the most prevalent and hardest to treat health burdens worldwide. Since pharmacological treatment with a single drug is often rather ineffective, approaches such as co-medication with functionally diverse antidepressants (ADs) have been discussed and tried more recently. Besides classical ADs, there is a growing number of candidate targets identified as potential starting points for new treatment methods. One of these candidates, the FK506 binding protein 51 (FKBP51) is linked to a number of psychiatric disorders in humans. In this study, we used SAFit2-a newly developed modulator of FKBP51, which has shown promising results in rodent models for stress-related disorders delivered in a depot formulation. We combined SAFit2 with the commonly prescribed selective serotonin reuptake inhibitor (SSRI) escitalopram and performed basic behavioral characterization in a mouse model. Remarkably, co-application of SAFit2 lowered the efficacy of escitalopram in anxiety-related tests but improved stress coping behavior. Given the fact that mental diseases such as anxiety disorders or depression can be divided into different sub-categories, some of which more or less prone to stress, SAFit2 could indeed be a highly beneficial co-medication in very specific cases. This study could be a first, promising step towards the use of FKBP51 modulators as potent and specific enhancers of AD efficiency for subclasses of patients in the future

Developmental ORIgins of Healthy and Unhealthy AgeiNg : The Role of Maternal Obesity - Introduction to DORIAN

Peer reviewe

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain

The effects of pre- and perinatal nicotine exposure and genetic background on histological and behavioural phenotypes

Approximately 11% of pregnant woman in Canada continue to use tobacco during pregnancy. Maternal tobacco use increases the risk of complications in pregnancy and also the risk of adverse foetal outcomes. Although tobacco smoke contains over 4000 compounds, studies have established nicotine as the principal component of tobacco smoke that leads to the majority of negative reproductive outcomes associated with maternal tobacco use. It appears the neuroteratogenicity of nicotine is mediated by complex gene-environment interactions. Genetic background contributes to individual differences in nicotine-related phenotypes. The aim of the current study was to investigate the interaction between pre- and perinatal nicotine exposure and genetic background on histological and behavioural measures using DBA/2J (D2) and C57BL/6J (B6) inbred mice. Alterations in neuronal cell populations, regional brain volumes, and behaviour - open field (OF) activity, novel object recognition (NOR), elevated plus maze (EPM), and passive avoidance (PA) - were evaluated on postnatal day (PN) 24 and PN75, following early exposure to nicotine solution (200 μg/ml)starting from 30 days before pregnancy up to pups weaning. Data revealed no difference between treatment groups of dams in gestational weight gain or pup mortality. Histological data showed that early nicotine exposure resulted in decreased striatal volume among preadolescent females and reduced neuronal number within the striatum of preadolescent B6 mice. In the hippocampus the effects of early nicotine exposure appeared more subtle, in which only the granule cell layer of the dentate gyrus in D2 preadolescents was afflicted. Behavioural data showed that early nicotine exposure promoted hyperactivity in D2 female mice and disrupted NOR and PA memory. Specifically, NOR deficits were significant amongst adult male mice whereas PA deficits were unconditional. These data suggest that pre- and perinatal nicotine affects regional brain morphology and leads to neurobehavioural alterations. The observed treatment interactions suggest that genetic background, developmental stage, and sex interact with nicotine to influence nicotine-related phenotypes.Medicine, Faculty ofGraduat

A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice

Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide. A polymorphism in FAAH (FAAH C385A) reduces FAAH expression, increases anandamide levels, and increases the risk of obesity. Nevertheless, some studies have found no association between FAAH C385A and obesity. We investigated whether the environmental context governs the impact of FAAH C385A on metabolic outcomes. Using a C385A knock-in mouse model, we found that FAAH A/A mice are more susceptible to glucocorticoid-induced hyperphagia, weight gain, and activation of hypothalamic AMP-activated protein kinase (AMPK). AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in agouti-related protein (AgRP) neurons mimicked the exaggerated feeding response of FAAH A/A mice to glucocorticoids. FAAH A/A mice likewise presented exaggerated orexigenic responses to ghrelin, while FAAH knockdown in AgRP neurons blunted leptin anorectic responses. Together, the FAAH A/A genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a putative mechanism explaining the diverging human findings