BDNF activates postsynaptic TrkB receptors to induce endocannabinoid release and inhibit presynaptic calcium influx at a calyx-type synapse.

Brain-derived neurotropic factor (BDNF) has been shown to play critical roles in neural development, plasticity, and neurodegenerative diseases. The main function of BDNF in the brain is widely accepted to be synaptic regulation. However, how BDNF modulates synaptic transmission, especially the underlying signaling cascades between presynaptic and postsynaptic neurons, remains controversial. A recent study demonstrated that BDNF slows presynaptic calcium current activation and inhibits synaptic transmission at a calyx-type synapse. However, tropomyosin receptor kinase B (TrkB) receptors, the major BDNF receptors, have both presynaptic and postsynaptic expression, and whether BDNF can retrogradely induce presynaptic inhibition via activation of postsynaptic TrkB receptors remains unclear. In the present study, we investigated this possibility by measuring the excitatory postsynaptic current (EPSC) and presynaptic calcium current and capacitance changes at rat calyces of either sex. We found that BDNF inhibits the EPSC, presynaptic calcium influx, and exo-endocytosis via activation of the presynaptic cannabinoid type 1 receptors (CB1Rs). Inhibition of the CB1Rs abolished the BDNF-induced presynaptic inhibition, whereas CB1R agonist mimicked the effect of BDNF. Exploring the underlying signaling cascade, we found that BDNF specifically activates the postsynaptic TrkB receptors, inducing the release of endocannabinoids via the PLCγ/DGL pathway and retrogradely activating presynaptic CB1Rs. We also reported the involvement of AC/PKA in modulating vesicle endocytosis, which may account for the BDNF-induced calcium-dependent and -independent regulation of endocytosis. Thus, our study suggests a different underlying mechanism than the previous study and provides new insights into the BDNF/endocannabinoid-associated modulation of neurotransmission in physiological and pathological processes. SIGNIFICANCE STATEMENT BDNF plays critical roles in the modulation of synaptic strength. However, how BDNF regulates synaptic transmission and its underlying signaling cascade(s) remains elusive. A previous study reported that BDNF slows presynaptic calcium current activation and inhibits exo-endocytosis, but an alternative interpretation that activation of postsynaptic TrkB receptors evokes the release of endocannabinoids to retrogradely inhibit the presynaptic calcium current has not been verified. By measuring the calcium current and capacitance changes at calyces, we confirm this alternative pathway. Activation of postsynaptic TrkB receptors induces endocannabinoid release, retrogradely activating the presynaptic CB1Rs, inhibiting the AC/PKA, and suppressing calcium influx. Our findings suggest a new interpretation of the previous study and provide a comprehensive understanding of BDNF/endocannabinoid-associated modulation of neuronal activities.