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, 62 (2), 628-37

PTSD and Gene Variants: New Pathways and New Thinking


PTSD and Gene Variants: New Pathways and New Thinking

Kelly Skelton et al. Neuropharmacology.


Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated - the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenergic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.


Figure 1
Figure 1. Fear neurocircuitry
This schematic diagram illustrates the interactions between the Hypothalamic-Pituitary-Adrenal (HPA) axis, the locus coeruleus and the amygdala intrinsic to the fear neurocircuitry within the brain. In response to stimuli indicating potential threat, the amygdala is activated to elaborate the fear response. One target of the output of the amygdala is activation of the HPA axis at the level of the paraventricular nucleus of the hypothalamus, which leads to the release of Corticotrophin Releasing Hormone (CRH). This hormone activates the pituitary to release Adrenocorticotrophin Hormone (ACTH), which is released into the systemic circulation to stimulate the production and release of cortisol from the adrenal cortex. Cortisol, amongst other functions, serves to increase glucose availability to be utilized as a metabolic resource during times of stress. Feedback inhibition of the HPA axis is mediated in part by the binding of cortisol to glucocorticoid receptors (GRs) to limit excessive activation of the HPA axis. In addition to innervation of the HPA axis, the amygdala also activates the locus coeruleus, the primary noradrenergic nucleus in the brain, in a pathway which utilizes CRH neurotransmission. Norepinephrine released from the locus coeruleus has been hypothesized to play a role in the consolidation of fear memories and additionally projects to the amygdala to further stimulate its activation in a positive feedback fashion.
Figure 2
Figure 2. Schematic of FKBP5 cellular function
This diagram illustrates the function of FKBP5 as a co-chaperone which regulates glucocorticoid receptor (GR) binding and translocation within the nucleus. When sufficient cortisol is present, GRs dimerize and FKBP5 is displaced, allowing GR translocation and transcriptional activation. In this manner, reduced activity of FKBP5 is associated with increased sensitivity of GRs, as is demonstrated in PTSD. Heat shock protein 90 = hsp90, another molecular co-chaperone which interacts with FKBP5. Figure courtesy of Elisabeth Binder, MD PhD.

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