New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

Figure 1 Schematic illustration of the activity-dependent regulators for Brain-derived neurotrophic factor gene transcription. A variety of transcriptional factors and regulators participate in the activity-induced transcription of BDNF. BDNF gene structure and Ca²⁺-dependent regulation in BDNF exon IV and epigenetic regulation at the exon IX promoter region are presented. We referred to the description by Zheng et al[38], also see[180]. BDNF: Brain-derived neurotrophic factor; CaRF: Calcium responsive factor; USF: Upstream stimulatory factors; BHLHB: Basic helix-loop-helix; CREB: Cyclic AMP-responsive element binding protein; NFκB: Nuclear factor-κB.

Figure 2 Schematic illustration of activity-dependent brain-derived neurotrophic factor secretion. A possible mechanism of intracellular Ca²⁺-dependent secretion of BDNF suggested in literature. Ca²⁺ influx through NMDA receptor/L-type VGCC and subsequent Ca²⁺ release of internal stores via ryanodine receptors are required for secretion. CaMKII, PKA, synaptotagmin IV, and CAPS2 also critically contribute to the membrane fusion process of BDNF-containing vesicles. VGCC: L-type voltage-gated calcium channels; CaMKII: calcium/calmodulin-dependent protein kinase II; PKA: protein kinase A; CAPS2: Ca²⁺-dependent activator protein for secretion 2; BDNF: Brain-derived neurotrophic factor.

Figure 3 Molecular mechanisms of phencyclidine-induced synaptic loss as a cellular model of schizophrenia. Phencyclidine decreased the number of synaptic sites in cultured cortical neurons through blockade of Ca²⁺ influx via NMDARs and resultant suppression of BDNF secretion. The impairment in BDNF secretion reduced TrkB activation and resulted in decreased synaptic connectivity[15]. BDNF: Brain-derived neurotrophic factor; NMDAR: N-methyl-D-aspartate receptors; PCP: Phencyclidine.