Loss of BDNF or its receptors in three mouse models has unpredictable consequences for anxiety and fear acquisition.

BDNF-induced signaling is essential for the development of the central nervous system and critical for plasticity in adults. Mature BDNF signals through TrkB, while its precursor proBDNF employs p75(NTR), resulting in activation of signaling cascades with opposite effects on neuronal survival, growth cone decisions, and synaptic plasticity. Accordingly, variations in the genes encoding BDNF and its receptors sometimes have opposing influences in psychiatric disorders, and despite the vast literature, consensus is lacking about the behavioral consequences of disrupting the activity of the BDNF system in mice. To dissect the behavioral traits affected by dysfunctional BDNF/TrkB vs. proBDNF/p75(NTR) activity, we studied Bdnf(+/-), Ntrk2(+/-), and Ngfr(-/-) mice in parallel with respect to exploratory behavior, anxiety, startle, and fear acquisition. Our data reveal that the effect of proBDNF/BDNF and its receptors on behavior is more complex than expected. Strikingly, receptor-deficient mice displayed increased risk-taking behavior in the open field and elevated plus maze, whereas lack of proBDNF/BDNF had the opposite effect on mouse behavior. On the other hand, although TrkB signaling is instrumental for acquisition of fear memory in an inhibitory avoidance experiment, lack of p75(NTR) or proBDNF/BDNF conferred increased memory in this task. Importantly, none of the genotypes displayed any deficits in startle reflex, indicating unimpaired response to shock. The combined data illustrate an apparent paradox in the role of the BDNF system in controlling complex behavior and suggest that the individual components may also engage independently in separate signaling pathways.