A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder

Abstract

Major depressive disorder (MDD) is a mood disorder that affects behavior and impairs cognition. A gene potentially important to this disorder is the brain derived neurotrophic factor (BDNF) as it is involved in processes controlling neuroplasticity. Various mechanisms exist to regulate BDNF's expression level, subcellular localization, and sorting to appropriate secretory pathways. Alterations to these processes by genetic factors and negative stressors can dysregulate its expression, with possible implications for MDD. Here, we review the mechanisms governing the regulation of BDNF expression, and discuss how disease-associated single nucleotide polymorphisms (SNPs) can alter these mechanisms, and influence MDD. As negative stressors increase the likelihood of MDD, we will also discuss the impact of these stressors on BDNF expression, the cellular effect of such a change, and its impact on behavior in animal models of stress. We will also describe epigenetic processes that mediate this change in BDNF expression. Similarities in BDNF expression between animal models of stress and those in MDD will be highlighted. We will also contrast epigenetic patterns at the BDNF locus between animal models of stress, and MDD patients, and address limitations to current clinical studies. Future work should focus on validating current genetic and epigenetic findings in tightly controlled clinical studies. Regions outside of BDNF promoters should also be explored, as should other epigenetic marks, to improve identification of biomarkers for MDD.

The role of BDNF methylation and Val66Met in amygdala reactivity during emotion processing

“…Furthermore, since determination of BDNF methylation in the brain of live patients is impractical, a direct correlation between BDNF methylation levels in the blood and brain cannot be assured. However, previous work indicates that BDNF can cross the blood–brain barrier, leading to detectable changes in peripheral blood (Hing, Sathyaputri, & Potash, ). Positive correlations between whole‐blood BDNF levels and hippocampal BDNF in rats and pigs were observed (Klein et al, ), underlining peripheral BDNF measurements as a useful predictor of neuronal BDNF appearance (Hing et al, ; Kundakovic et al, ).…”

“…However, previous work indicates that BDNF can cross the blood–brain barrier, leading to detectable changes in peripheral blood (Hing, Sathyaputri, & Potash, ). Positive correlations between whole‐blood BDNF levels and hippocampal BDNF in rats and pigs were observed (Klein et al, ), underlining peripheral BDNF measurements as a useful predictor of neuronal BDNF appearance (Hing et al, ; Kundakovic et al, ). The not significant BDNF polymorphism effects on the amygdala and personality trait level might be due to the low amount of Met/Met allele ( n = 8) carriers and the resulting combination of Met/Met and Val/Met carriers into one group.…”

An improved CRISPR/dCas9 interference tool for neuronal gene suppression

“…Lentiviral expression of sgRNAs targeting this system to unique gene promoters produced robust knockdown at multiple gene targets in two neuronal culture platforms. This optimized CRISPRi system also enabled transcript-specific manipulations at the Bdnf gene locus, revealing efficient silencing of a complex target relevant to learning, memory, and neuropsychiatric disease 59,[63][64][65][66][67][68][69][70] . It is worth highlighting the extent of gene depletion achieved by a single sgRNA in these experiments.…”

The Role of BDNF in the Pathogenesis of Neurological and Mental Disorders

“…Показаны значимые корреляции между уровнями BDNF в сыворотке крови и депрессивными состояниями и ассоциации концентрации нейротрофина с успешностью антидепрессивной терапии. У пациентов с депрессией наблюдается снижение уровня BDNF в сыворотке и гиппокампе и его восстановление при длительном приеме антидепрессантов[13]. Практически все антидепрессанты улучшают нейрогенез и зачастую повышают концентрацию нейротрофических факторов, что поддерживает гипотезу нейрогенеза.Salinas J. et al[32] показали, что наличие эмоциональной поддержки связано с повышенным уровнем BDNF в сыворотке и сниженным риском развития деменции и инсульта, в то время как только уровень BDNF вносит небольшой вклад в развитие этих заболеваний.…”