Application of exogenous BDNF to the optic tectum rapidly and profoundly impacts the retinotectal circuit. In vivo imaging of puncta of the synaptic vesicle protein GFP-synaptobrevin in Xenopus retinotectal Dabrafenib price axons has revealed a rapid increase in axonal branching and presynaptic punctum number within minutes to hours of BDNF application ( Alsina et al.,

2001 and Hu et al., 2005). A BDNF-mediated increase in the number of PSD95-GFP positive postsynaptic specializations appears to occur subsequent to presynaptic changes, becoming evident only many hours after neurotrophin application ( Sanchez et al., 2006). Functionally, a rapid increase in mEPSC frequency, but not amplitude, has been reported in response to application of BDNF to the tectum ( Du and Poo, 2004). Our experimental protocol differed from these approaches in two important ways. First, the elevation of BDNF levels in our experiments relied on activity-dependent synthesis and release of endogenous protein rather than application of exogenous neurotrophin. Second, the BDNF-mediated changes that we described occurred only in response to specific

LTP- and LTD-inducing electrical and visual stimulation protocols. Thus, the specific timing and location of neurotrophin delivery may determine its effects on the circuit. This is consistent Fulvestrant solubility dmso with the report that the human BDNF val66met polymorphism which impairs dendritic trafficking and activity-dependent, but not constitutive secretion of BDNF results in abnormal hippocampal function ( Egan et al., 2003). While our own experiments do not distinguish between

pre- and postsynaptic sites of action of the BDNF synthesized in response to visual conditioning stimuli, the efficacy with which MO knockdown of tectal BDNF synthesis fully prevented facilitation of both LTP and LTD clearly points to the postsynaptic cell as the source of newly synthesized BDNF. Retinotectal LTP experiments by Du and colleagues (2009) using MO antisense Endonuclease against TrkB targeted to presynaptic retinal or postsynaptic tectal neurons suggested that BDNF signaling onto both synaptic partners contributed to BDNF-dependent LTP expression. Quite remarkably, this same study also observed a retrograde change in synaptic transmission back in the retina within minutes of BDNF applied exclusively to the tectum. It is clear from our optic chiasm stimulation experiments that endogenous BDNF directly facilitated plasticity at the retinotectal synapse. While we cannot exclude the additional possibility that the newly synthesized BDNF may also have had retrograde effects in the retina that could have contributed to the refinement of visually evoked and behavioral responses that we observed, we did not detect changes in proBDNF levels in the retinae of tadpoles that had undergone visual conditioning (Figure S1).