Does bdnf val66met attenuate the efficacy of antidepressant induced increases in hippocampal neurogenesis?

Society for Neuroscience. 2008.


Brain-derived neurotrophic factor (BDNF) is a critical regulator of many aspects of adult plasticity, and has been proposed as a target molecule for antidepressant response. Nearly all antidepressant regimens tested to date increase BDNF within the adult brain. Furthermore, in animal models, infusion of BDNF itself into the brain has antidepressant effects. This has led some to propose that augmentation of BDNF signaling via antidepressant treatment may be a critical process for antidepressant response, termed "the neurotrophic hypothesis of depression". The neurotrophic hypothesis is particularly relevant given the recent discovery of a uniquely human single nucleotide polymorphism (SNP) in the bdnf gene (Val66Met), which interferes with BDNF trafficking and results in ineffective regulated release of BDNF from neurons. In animal models of depression, one potential target of increased trophic support is through augmentation of hippocampal neurogenesis, a process impacted by altered BDNF levels. We have recently generated a mouse model in which we have knocked-in the BDNF Val66Met SNP and demonstrated that these mice phenocopy human carriers of the Val66Met SNP, and in addition, these mice show elevations in anxiety-like behavior. Furthermore, these mice show a blunted behavioral response to chronic antidepressant treatment in a novelty induced hypophagia task, a task that is predictive of antidepressant response in humans. As an initial attempt to uncover the mechanisms underlying this blunted behavioral response we tested for changes in rates of cell proliferation and survival in the hippocampi of BDNF Val66Met mice following chronic administration of fluoxetine. Our initial results indicate that chronic fluoxetine treatment leads to increased neurogenesis in both wildtype and mice homozygous for the BDNF Val66Met SNP. However, similar to our previous behavioral results, despite showing increased neurogenesis, mice homozygous for the BDNF Met polymorphism never reached the same level of neurogenesis observed in fluoxetine treated wildtype mice. These data provide one potential mechanism by which BDNF Val66Met may confer a blunted response to antidepressants.