BDNF Modulates Presynaptic Functions at a Central Synapse

Abstract

Our brain function relies on the communication between neurons, a process called synaptic transmission. Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates synaptic transmission in many brain areas and thus may critically influence brain function. The synaptic effect of BDNF may contribute to its well-known roles in regulation of neuronal survival, synapse development, and synaptic plasticity. Despite these important roles, the basic mechanism by which BDNF affects synaptic transmission remains poorly understood. Previous studies suggest that BDNF acts on transmitter release at nerve terminals, the presynaptic component of the synapse. However, the mechanism by which BDNF regulates transmitter release is unclear. In this study we investigate the role of BDNF in presynaptic function by electrophysiological recordings at the calyx of Held nerve terminal. The calyx of Held is a glutamatergic synapse in the auditory brainstem with a large nerve terminal, which allows direct presynaptic patch-clamp recording and membrane capacitance measurement. By recording vesicle fusion with capacitance measurements at this synapse, here we show that acute application of BDNF inhibits exocytosis. This effect is specific to BDNF because application of K252a, an inhibitor of the BDNF receptor, TkB, blocks the actions of BDNF on presynaptic function. Moreover, BDNF inhibits rapid and slow endocytosis, thus providing a regulatory mechanism for vesicle recycling. Furthermore, we recorded the presynaptic calcium current directly at the calyx nerve terminal and found for the first time that BDNF inhibits calcium current. It has been shown previously, that both exo- and endocytosis are regulated by calcium influx. Thus, our findings establish that neurotrophins regulate the function of the nerve terminal via presynaptic calcium channels. Further understanding of these mechanisms will advance our knowledge of synaptic transmission regulation, a process essential for our brain function.