Long-term memory and synaptic plasticity require changes in gene expression and yet can occur in a synapse-specific manner. mRNA localization and regulated translation at synapses are thus critical for establishing synapse specificity. Using live cell microscopy of photoconvertible fluorescent protein translational reporters, we directly visualized local translation at synapses during long-term facilitation of Aplysia sensory-motor synapses. Translation of the reporter required multiple applications of serotonin, was spatially restricted to stimulated synapses, was transcript-and stimulus-specific, and occurred during long-term facilitation but not during longterm depression of sensory-motor synapses. Translational regulation only occurred in the presence of a chemical synapse and required calcium signaling in the postsynaptic motor neuron. Thus highly regulated local translation occurs at synapses during long-term plasticity and requires transsynaptic signals.Long-lasting learning-related synaptic plasticity requires transcription for its persistence (1-3) and yet can occur in a synapse-specific manner (4-7). One mechanism that has been proposed to mediate this spatial restriction of gene expression during neuronal plasticity involves regulated translation of localized mRNAs at stimulated synapses (8-10). Many findings support the existence of local translation at synapses. First, all of the machinery required for translation is present in neuronal processes, including polyribosomes (11,12), translation factors (13), and a select population of mRNAs (14-18). Second, studies using

A localized transcriptome at the synapse facilitates synapse-, stimulus- and transcript-specific local protein synthesis in response to neuronal activity. While enzyme-mediated mRNA modifications are known to regulate cellular mRNA turnover, the role of these modifications in regulating synaptic RNA has not been studied. We established low-input mA-sequencing of synaptosomal RNA to determine the chemically modified local transcriptome in healthy adult mouse forebrains and identified 4,469 selectively enriched mA sites in 2,921 genes as the synaptic mA epitranscriptome (SME). The SME is functionally enriched in synthesis and modulation of tripartite synapses and in pathways implicated in neurodevelopmental and neuropsychiatric diseases. Interrupting mA-mediated regulation via knockdown of readers in hippocampal neurons altered expression of SME member Apc, resulting in synaptic dysfunction including immature spine morphology and dampened excitatory synaptic transmission concomitant with decreased clusters of postsynaptic density-95 (PSD-95) and decreased surface expression of AMPA receptor subunit GluA1. Our findings indicate that chemical modifications of synaptic mRNAs critically contribute to synaptic function.

mRNA localization and regulated translation provide a means of spatially restricting gene expression within each of the thousands of subcellular compartments made by a neuron, thereby vastly increasing the computational capacity of the brain. Recent studies reveal that local translation is regulated by stimuli that trigger neurite outgrowth/collapse, axon guidance, synapse formation, pruning, activity-dependent synaptic plasticity, and injury induced axonal regeneration. Impairments in the local regulation of translation result in aberrant signaling, physiology, and morphology of neurons, and are linked to neurological disorders. This review highlights current advances in understanding how mRNAs are translationally repressed during transport and how local translation is activated by stimuli. We address the function of local translation in the context of fragile X mental retardation.