FIGURE 3 | The yin and yang of long-term synaptic regulation by pro- and mature BDNF

a | Molecular cascade of brain-derived neurotrophic factor (BDNF) processing in late-phase long-term potentiation (L-LTP). In response to theta-burst stimulation (TBS), tissue plasminogen activator (tPA) is secreted into the synaptic cleft and cleaves the extracellular protease plasminogen to yield plasmin (1). Plasmin then cleaves proBDNF (the precursor of BDNF, which is released in an activity-dependent manner), yielding mature BDNF (mBDNF) (2). mBDNF binds to TrkB and triggers a series of downstream signalling pathways to induce LTP (3). During the maintenance stage of LTP, mBDNF might be generated by intracellular cleavage after postsynaptic transcription and translation (4). By contrast, proBDNF secreted extracellularly remains uncleaved after low-frequency stimulation (LFS). Uncleaved proBDNF binds to the p75 neurotrophin receptor (p75^NTR) (5) to facilitate the induction of long-term depression (LTD), possibly through the regulation of NMDA (N-methyl-D-aspartate) receptor NR2B subunit expression. b | Morphological alterations in synapses induced by pro- and mature BDNF. Left, BDNF–Trk signalling might be an active mechanism that converts activity-induced molecular signals into structural plasticity, contributing to synapse formation. Right, proBDNF–p75^NTR signalling might be important in translating activity-dependent signals into negative modulation of structural plasticity, contributing to synapse retraction.

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