FIGURE 1.

The interplay between genetic and environmental factors modulates the expression of the BDNF variants. BDNF gene expression is controlled at many levels. The inclusion of particular exons and the differential use of polyadenylation sites and/or starting codons modify not only the BDNF variant but also the temporal dynamics of its expression through the modification, for instance, of the stability of the BDNF mRNA. Variability at any of these levels of regulation can lead to differential levels of mature BDNF in healthy or diseased subjects. These differences could be related to genetic (i.e., Val66Met and other polymorphisms) or environmental factors (chronic stress, exercise, and amongst others). In addition to correlational studies performed in humans, the use of non-human animal models, particularly rodent models, can lead to establish certain relationships schematized above between these factors. Blunt arrows indicate that a decrease in BDNF expression and the sharped ones symbolize the opposite pattern. Although the consensus agrees that aging, the development of Alzheimer’s disease and the exposure to chronic stress are related to reductions in BDNF levels, some studies could not find those associations or found the opposite pattern (cases represented with dashed lines). On the other hand, some external interventions are able to enhance BDNF expression, such as exercise, enriched environment and antidepressants. For this reason, the aforementioned interventions could be potential treatments for cognitive impairments related to low BDNF expression. Since these external factors can interact with each other (represented by the orange circular arrow), it is important to take into account all of these potential interactions at the time of determining causal links between the effects of any of these variables on BDNF expression.