Li Y et al. (2008) TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 59: 399–412

Scientists in the US have come closer to understanding why antidepressants do not always work—a poor treatment response could be related to impairment of TrkB-dependent neurogenesis in the forebrain.

More than a third of patients with depression do not respond to first-line treatment with current antidepressants. Previous research has indicated that neurogenesis might be a key requirement for these drugs to be effective; furthermore, brain-derived neurotrophic factor (BDNF) has been suggested to have a role in mediating the response to chronic antidepressant therapy. Research by Li et al. now shows that a functional link exists between these two mechanisms. In mice, ablation of TrkB (the gene that encodes a receptor for BDNF) in hippocampal neurogenic progenitor cells resulted in impaired neurogenesis and prevented the behavioral improvements associated with chronic antidepressant therapy that were seen in wild-type animals. Of note, deletion of TrkB in fully differentiated neurons of the same brain regions had no such effects.

Voluntary exercise can have effects on neurogenesis and behavior that are similar to those observed with chronic antidepressant therapy; therefore, Li et al. conducted a control experiment that studied the effects of TrkB deletion on the biological and behavioral responses to wheel running. The results confirmed the findings above. Further in vivo and in vitro observations suggested that reduced neurogenesis in the absence of TrkB is caused by a decrease in BDNF-induced proliferation of hippocampal precursor neurons.

Luis Parada, senior author of the study, concludes that “in a genetic model system, hippocampal neurogenesis is required to mediate chronic antidepressive effects. This may help explain why antidepressants only have beneficial effects after chronic treatment despite their immediate pharmacological activity upon consumption.”