These increased levels of proBDNF, as well as an accompanying enhancement

of signaling downstream selleck inhibitor of mBDNF, did not appear to induce synaptic changes on their own, but rather facilitated ongoing plasticity mechanisms. Importantly, enhanced BDNF signaling contributed to a behaviorally detectable improvement in visual acuity. In summary, our findings reveal that the BDNF synthesized in response to 20 min of visual conditioning can facilitate bidirectional plasticity at the retinotectal synapse with direct behavioral consequences for the developing animal. A summary is presented in Figure 7. Recent studies, carried out mainly in the CA1 area of mouse hippocampus, have revealed key roles for BDNF signaling and processing in synaptic LTP and LTD. Late-phase LTP (L-LTP) in CA1 is largely absent in transgenic mice lacking BDNF, and early-phase LTP is Paclitaxel ic50 also substantially reduced in these animals (Korte et al., 1995 and Patterson et al., 1996). Neurons are able to release both the precursor and mature forms of BDNF; however, the site of release may be a critical determinant of what form the released protein takes (Matsuda et al., 2009 and Yang et al., 2009). As the protein synthesis machinery present in most dendrites lacks the Golgi-like organelles that process constitutively secreted proteins (Horton et al.,

2005), it is likely that dendritically synthesized BDNF is secreted in its precursor form (An

et al., 2008). Secreted proBDNF at synapses would then be cleaved to mBDNF by plasmin, activated from plasminogen by the activity of tPA, consistent with reports that tPA is also required for L-LTP (Pang et al., 2004). Our findings in the retinotectal system suggest a similar requirement for the synaptic release and cleavage of proBDNF, as acute inhibition of tPA activity reduced retinotectal LTP to the same degree as pharmacological inhibition of TrkB signaling. Furthermore, the knockdown of BDNF by MO antisense electroporation into tectal neurons reveals that BDNF from the postsynaptic cell is required for LTP. On the other hand, the activation of the p75NTR by proBDNF has been reported to facilitate hippocampal LTD (Woo et al., 2005). Our retinotectal all data confirmed the facilitation of LTD by recently synthesized proBDNF, and demonstrated that this could be mimicked by exogenous application of proBDNF if tPA activity is inhibited. In light of these findings, it is interesting to consider how the regulation of the rate of proBDNF cleavage could regulate not only the efficacy but also the direction of synaptic plasticity (Nagappan et al., 2009). In contrast to these findings during development, inhibiting BDNF signaling in the mature visual cortex does not appear to affect plasticity, but rather reduces responsiveness to high-spatial frequency stimuli (Heimel et al., 2010).