Neuroplasticity is an important feature of mammalian brains, referring to the functional or structural changes of the nervous system after learning or adapting to the changes of environment. Activity-dependent transcription is critical for neuroplasticity. Brain-derived neurotrophic factor, an activity-dependent gene, has emerged as a key molecule in synaptic plasticity, memory formation and neurological diseases. The regulation of activity-dependent BDNF transcription remains elusive.Exon IV-containing BDNF mRNA (BDNF IV) is one of the major activity-responsive forms of the multiple BDNF mRNAs. Calcium influx via calcium channel or NMDA receptor stimulates BDNF IV transcription in cortical neurons, which requires activity of MAPK, PI3K, PKA and CaMKs. The three identified calcium-responsive elements (CaREs) in the BDNF IV promoter (promoter IV) mediate calcium-induced BDNF IV transcription coordinately. In mature neurons, only CaRE1 and CaRE3 are responsive to calcium influx and are regulated by MAPK, PI3K and CaMKs in a stimulation-selective manner.BDNF IV is also induced by self-stimulation, which is regulated by MAPK activity, extra- and intracellular calcium level and the NMDA receptor. Both NR2A-and NR2B-containing NMDA receptors, as well as synaptic and extrasynaptic NMDA receptor, are required for BDNF self-induction. Moreover, a synergistic effect of BDNF and NMDA stimulation has been found for BDNF IV upregulation.In summary, we suggest a novel working model for the regulation of calcium- and BDNF-induced BDNF transcription.
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