BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity

Abstract

Bipolar disorder (BD) and post-traumatic stress disorder (PTSD) frequently co-occur among psychiatric patients, leading to increased morbidity and mortality. Brain-derived neurotrophic factor (BDNF) function is associated with core characteristics of both BD and PTSD. We propose a neurobiological model that underscores the role of reduced BDNF function resulting from several contributing sources, including the met variant of the BDNF val66met (rs6265) single-nucleotide polymorphism, trauma-induced epigenetic regulation and current stress, as a contributor to the onset of both illnesses within the same person. Further studies are needed to evaluate the genetic association between the val66met allele and the BD-PTSD population, along with central/peripheral BDNF levels and epigenetic patterns of BDNF gene regulation within these patients.

Figure 1

The brain-derived neurotrophic factor (BDNF) gene. The gene is comprised of eight 5′-untranslated exon regions linked to individual promoter regions and one protein coding 3′ exon. The linked complex polymorphic region (LCPR) is located 1.0 kb upstream of the translation initiation site. It consists of three types of dinucleotide repeats, insertion/deletion and nucleotide substitutions resulting in 23 unique allelic variants. The val66met single-nucleotide polymorphism (SNP) is located within the coding region. Hatch marks represent intron regions that are spliced out of the final protein product.

Figure 2

A putative model linking trauma and brainderived neurotrophic factor (BDNF) function to the development of bipolar disorder and post-traumatic stress disorder. Patients may carry genetic risk factors, including BDNF val66met single-nucleotide polymorphism (SNP) variants, BDNF-linked complex polymorphic region (LCPR) allelic variants and other unidentified markers increasing their risk for altered BDNF protein production^, and bipolar illness.^,, Exposure to early childhood trauma may induce epigenetic modification in the form of histone and DNA acetylation and methylation, leading to further reductions of BDNF protein production. This may trigger the onset of bipolar illness in the form of depressive and manic episodes.^– Adulthood trauma may occur, once again interrupting BDNF production.^– Reduced BDNF function may interfere with fear extinction leading to the development of post-traumatic stress disorder (PTSD)^– and increased emotion dysregulation. This could lead to a worsening course of bipolar illness, in the form of increased mood episodes over time, followed by further reductions in BDNF levels. Abbreviations: D, depressive episodes; M, manic episodes.