Brain‐derived neurotrophic factor (BDNF) has been implicated in the potent modulation of synaptic plasticity at both pre‐synaptic and post‐synaptic sites. However, the molecular mechanism underlying BDNF‐mediated pre‐synaptic modulation remains incompletely understood. Here, we report that BDNF treatment for over 4 h could significantly enhance the expression of c‐Jun NH2‐terminal kinase‐interacting protein 3 (JIP3) in cultured hippocampal neurons. This enhancement could be blocked by the Trk inhibitor K252a or by a cAMP response element‐binding protein (CREB) inhibitor. In addition, chromatin immunoprecipitation (ChIP) assays revealed that CREB could bind with the JIP3 promoter region and the BDNF treatment could increase this binding. Using dual‐luciferase assays we further characterized the cAMP response element (CRE) site in the JIP3 promoter. Finally, we found that BDNF‐increased JIP3 expression contributes to the BDNF‐induced modulation of neurotransmitter release. Together, our studies reveal that in hippocampal neurons BDNF up‐regulates JIP3 expression via CREB activation, which contributes to the enhancement of neurotransmitter release; thus, we have identified a novel mechanism that BDNF modulates pre‐synaptic transmission.
We demonstrated that in hippocampal neurons BDNF/TrkB signaling mediates transcriptional up‐regulation of c‐Jun NH2‐terminal kinase‐interacting protein 3 (JIP3) via CREB activation. The up‐regulation of JIP3 further contributes to BDNF‐enhanced neurotransmitter release. These findings provide insight into the mechanistic link between BDNF‐mediated gene expression and its more sustained pre‐synaptic modulation, which may help us to further understand the roles of BDNF in neuronal plasticity.