Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain

Abstract

Brain Derived Neurotrophic Factor (BDNF) is a key molecule involved in plastic changes related to learning and memory. The expression of BDNF is highly regulated, and can lead to great variability in BDNF levels in healthy subjects. Changes in BDNF expression are associated with both normal and pathological aging and also psychiatric disease, in particular in structures important for memory processes such as the hippocampus and parahippocampal areas. Some interventions like exercise or antidepressant administration enhance the expression of BDNF in normal and pathological conditions. In this review, we will describe studies from rodents and humans to bring together research on how BDNF expression is regulated, how this expression changes in the pathological brain and also exciting work on how interventions known to enhance this neurotrophin could have clinical relevance. We propose that, although BDNF may not be a valid biomarker for neurodegenerative/neuropsychiatric diseases because of its disregulation common to many pathological conditions, it could be thought of as a marker that specifically relates to the occurrence and/or progression of the mnemonic symptoms that are common to many pathological conditions.

Keywords: Alzheimer disease; BDNF; depression; hippocampus; memory; perirhinal cortex; stress.

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.