Elucidating the Role of Brain-Derived Neurotrophic Factor in the Brain

Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain and regulates diverse aspects of neuronal function. However, the specific mechanisms whereby BDNF regulates complex behavior have been difficult to assess because of a lack of pharmacological tools selective for BDNF and the low viability of the BDNF knockout mouse. Partial (but viable) BDNF knockout animals, where gene expression is reduced at an early developmental stage, mix the effects of the BDNF depletion itself with the developmental abnormalities caused by low BDNF.

To study BDNF function in the adult brain, we developed an inducible mouse BDNF knockout, illustrated in the figure (A, B), where BDNF expression can be blocked at specific developmental times and in defined brain regions. Moreover, in this knockout animal, BDNF is not entirely deleted, but its levels are diminished. In the adult mouse BDNF knockout, BDNF reductions can be demonstrated in neurons of the neocortex and the hippocampus (C, D). Behavioral studies with this inducible knockout animal show that BDNF has distinguishable functions if depleted during early development (e.g., extreme impairments in learning and memory) compared with depletion only in the adult brain (e.g., measurable but less extensive impairments). The adult reduction in BDNF results in diminished long-term potentiation in the hippocampus, the process that is believed to be the cellular mechanism of learning and memory (E) and in alterations in memory performance in the knockout mice. Curiously, reductions in BDNF in adult animals show gender-specific differences in motor and depression behaviors. Specifically, adult male BDNF knockouts show hyperactivity without depression behavior, whereas the female knockout mice show no motor changes but they express depression behaviors. It may be the case that the loss of BDNF increases the vulnerability of cerebral systems to adverse environmental events and decreases overall neural resilience.