Sam68 Enables Metabotropic Glutamate Receptor-Dependent LTD in Distal Dendritic Regions of CA1 Hippocampal Neurons.

The transport and translation of dendritic mRNAs by RNA-binding proteins (RBPs) allows for spatially restricted gene expression in neuronal processes. Although local translation in neuronal dendrites is now well documented, there is little evidence for corresponding effects on local synaptic function. Here, we report that the RBP Sam68 promotes the localization and translation of Arc mRNA preferentially in distal dendrites of rodent hippocampal CA1 pyramidal neurons. Consistent with Arc function in translation-dependent synaptic plasticity, we find that Sam68 knockout (KO) mice display impaired metabotropic glutamate-receptor-dependent long-term depression (mGluR-LTD) and impaired structural plasticity exclusively at distal Schaffer-collateral synapses. Moreover, by using quantitative proteomics, we find that the Sam68 interactome contains numerous regulators of mRNA translation and synaptic function. This work identifies an important player in Arc expression, provides a general framework for Sam68 regulation of protein synthesis, and uncovers a mechanism that enables the precise spatiotemporal expression of long-term plasticity throughout neurons.

Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation.

Previous evidence has suggested that dietary supplementation with a bioactive dietary polyphenol preparation (BDPP) rescues impairment of hippocampus-dependent memory in a mouse model of sleep deprivation (SD). In the current study, we extend our previous evidence and demonstrate that a mechanism by which dietary BDPP protects against SD-mediated cognitive impairment is via mechanisms that involve phosphorylation of the mammalian target of rapamycin complex 1 and its direct downstream targets, including the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase ß-1 (p70S6K). In additional mechanistic studies in vitro, we identified the brain bioavailable phenolic metabolites derived from the metabolism of dietary BDPP that are responsible for the attenuation of SD-mediated memory impairments. On the basis of high-throughput bioavailability studies of brain bioavailable metabolites after dietary BDPP treatment, we found that select polyphenol metabolites [ e.g., cyanidin-3'- O-glucoside and 3-(3'-hydroxyphenyl) propionic acid] were able to rescue mTOR and p70S6K phosphorylation in primary cortico-hippocampal neuronal cultures, as well as rescue 4E-BP1 phosphorylation in response to treatment with 4EGI-1, a specific inhibitor of eIF4E-eIF4G interaction. Our findings reveal a previously unknown role for dietary polyphenols in the rescue of SD-mediated memory impairments via mechanisms involving the promotion of protein translation.-Frolinger, T., Smith, C., Cobo, C. F., Sims, S., Brathwaite, J., de Boer, S., Huang, J., Pasinetti, G. M. Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation.