Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp

One of the cardinal features of neural development and adult plasticity is the contribution of activity-dependent signaling pathways. However, the interrelationships between different activity-dependent genes are not well understood. The immediate early gene neuronal-activity-regulated pentraxin (NPTX2 or Narp) encodes a protein that has been associated with excitatory synaptogenesis, AMPA receptor aggregation, and the onset of critical periods. Here, we show that Narp is a direct transcriptional target of brain-derived neurotrophic factor (BDNF), another highly regulated activity-dependent gene involved in synaptic plasticity. Unexpectedly, Narp is bidirectionally regulated by BDNF. Acute BDNF withdrawal results in downregulation of Narp, whereas transcription of Narp is greatly enhanced by BDNF. Furthermore, our results show that BDNF directly regulates Narp to mediate glutamatergic transmission and mossy fiber plasticity. Hence, Narp serves as a significant epistatic target of BDNF to regulate synaptic plasticity during periods of dynamic activity. [Display omitted] •The activity-dependent gene Narp is directly regulated by BDNF•Transcription of the Narp gene is mediated by TrkB signaling and CREB binding•Narp is required for BDNF regulation of glutamatergic transmission•Narp mediates mossy fiber LTP and BDNF-induced enhancement of mossy fiber LTP BDNF is responsible for many changes in synaptic plasticity in the brain, and its levels have an impact on neurodegenerative and psychiatric disorders. Narp is a synaptic protein that is highly responsive to BDNF. Here, Mariga et al. report how different levels of BDNF and Narp can change the plasticity of the mossy fiber/CA3 synapse.