Presynaptic FMRP and Local Protein Synthesis Support Structural and Functional Plasticity of Glutamatergic Axon Terminals

Abstract

Learning and memory rely on long-lasting, synapse-specific modifications. While postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remains unclear. Here, we examined the hippocampal mossy fiber (MF)-CA3 synapse which expresses both structural and functional presynaptic plasticity and contains presynaptic Fragile X mental retardation protein (FMRP), an RNA-binding protein previously implicated in local postsynaptic protein synthesis-dependent plasticity. We report that MF boutons contain ribosomes and synthesize protein locally. Long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with translation-dependent enlargement of MF boutons. Remarkably, increasing in vitro or in vivo MF activity enhanced protein synthesis in MFs. Moreover, deletion of presynaptic Fragile X mental retardation protein (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.