Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals

Learning and memory rely on long-lasting, synapse-specific modifications. Although postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remain unclear. Here, we examined the mouse hippocampal mossy fiber (MF)-CA3 synapse, which expresses both structural and functional presynaptic plasticity and contains presynaptic fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein involved in postsynaptic protein-synthesis-dependent plasticity. We report that MF boutons contain ribosomes and synthesize protein locally. The long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with the translation-dependent enlargement of MF boutons. Remarkably, increasing in vitro or in vivo MF activity enhanced the protein synthesis in MFs. Moreover, the deletion of presynaptic FMRP blocked structural and functional MF-LTP, suggesting that FMRP is a critical regulator of presynaptic MF plasticity. Thus, presynaptic FMRP and protein synthesis dynamically control presynaptic structure and function in the mature mammalian brain. [Display omitted] •Mossy fiber boutons (MFBs) contain ribosomes and synthesize protein locally•Local presynaptic translation is increased by in vitro and in vivo GC activity•MFB structural plasticity relies on de novo protein synthesis•Presynaptic FMRP is required for MF-CA3 structural and functional plasticity Monday, Kharod et al. report that neuronal activity regulates presynaptic FMRP function and the local synthesis of β-actin. In vitro activity and in vivo experience engage the FMRP-dependent spatiotemporal regulation of protein synthesis that is required for presynaptic remodeling and long-term changes in neurotransmitter release.