Some forms of synaptic plasticity require rapid, local activation of protein synthesis. Although this is thought to reflect recruitment of mRNAs to free ribosomes, this would limit the speed and magnitude of translational activation. Here we provide compelling in situ evidence supporting an alternative model in which synaptic mRNAs are transported as stably paused polyribosomes. Remarkably, we show that metabotropic glutamate receptor activation allows the synthesis of proteins that lead to a functional long-term depression phenotype even when translation initiation has been greatly reduced. Thus, neurons evolved a unique mechanism to swiftly translate synaptic mRNAs into functional protein upon synaptic signaling using stalled polyribosomes to bypass the ratelimiting step of translation initiation. Because dysregulated plasticity is implicated in neurodevelopmental and psychiatric disorders such as fragile X syndrome, this work uncovers a unique translational target for therapies.M ost studies of translational control focus on initiation, the process where mRNAs recruit ribosomes and catalyze the first step of translation (1). This highly regulated and normally rate-limiting step of translation is followed by elongation and termination, resulting in completed proteins. Although multiple ribosomes on a given mRNA (a polyribosome) imply active peptide synthesis, we and others identified neuronal RNA granulesmotile aggregates of nontranslating ribosomes (2, 3). These electron-dense bodies contain single copies of synaptic mRNAs that are translationally silenced during their transport from soma to synapse (1, 4).Many models assume that neuronally transported mRNAs are translationally paused before completion of the initiation step of translation during transport. An appropriate synaptic signal would then activate translation (initiation/elongation/termination) of the granule mRNA. However, it is not clear how many free ribosomal subunits are present at synapses to support translation initiation. Further, at a typical translation elongation rate of six amino acids per s (5, 6), synthesis of larger synaptic proteins (e.g., microtubule-associated protein 1b; MAP1b) would take over 5 min even if initiation were immediate. These two factors constrain the speed and magnitude of synaptic translation and, thus, plasticity. As some forms of synaptic plasticity require rapid (<10 min) and localized activation of protein synthesis, an alternative model is wanting (7-9).We have previously proposed the concept of a neuronal RNA granule as a stalled polyribosome (10, 11). Ribosomal stalling has been shown to occur in lysates from a mouse neuroblastoma cell line and in an in vitro rabbit reticulocyte lysate translation assay programmed with brain homogenate (12). Whether neuronal ribosome stalling occurs in vivo is uncertain. We hypothesized that neuronal RNA granules contain paused ribosomes with incomplete proteins initiated in the soma before their packaging and transport to dendrites, where translation can be rapidly and loca...

Cortical GABAergic interneurons represent a highly diverse neuronal type that regulates neural network activity. In particular, interneurons in the hippocampal CA1 oriens/alveus (O/A-INs) area provide feedback dendritic inhibition to local pyramidal cells and express somatostatin (SOM). Under relevant afferent stimulation patterns, they undergo long-term potentiation (LTP) of their excitatory synaptic inputs through multiple induction and expression mechanisms. However, the cell-type specificity of these different forms of LTP and their specific contribution to the dynamic regulation of the CA1 network remain unclear. Here we recorded from SOM-expressing interneurons (SOM-INs) in the O/A region from SOM-Cre-Ai3 transgenic mice in whole-cell patch-clamp. Results indicate that, like in anatomically identified O/A-INs, theta-burst stimulation (TBS) induced a Hebbian form of LTP dependent on metabotropic glutamate receptor type 1a (mGluR1a) in SOM-INs, but not in parvalbumin-expressing interneurons, another mainly nonoverlapping interneuron subtype in CA1. In addition, we demonstrated using field recordings from transgenic mice expressing archaerhodopsin 3 selectively in SOM-INs, that a prior conditioning TBS in O/A, to induce mGluR1a-dependent LTP in SOM-INs, upregulated LTP in the Schaffer collateral pathway of pyramidal cells. This effect was prevented by light-induced hyperpolarization of SOM-INs during TBS, or by application of the mGluR1a antagonist LY367385, indicating a necessity for mGluR1a and SOM-INs activation. These results uncover that SOM-INs perform an activity-dependent metaplastic control on hippocampal CA1 microcircuits in a cell-specific fashion. Our findings provide new insights on the contribution of interneuron synaptic plasticity in the regulation of the hippocampal network activity and mnemonic processes.

Neuronal mRNAs can be packaged in reversibly stalled polysome granules before their transport to distant synaptic locales. Stimulation of synaptic metabotropic glutamate receptors (mGluRs) reactivates translation of these particular mRNAs to produce plasticity-related protein; a phenomenon exhibited during mGluR-mediated LTD. This form of plasticity is deregulated in Fragile X Syndrome, a monogenic form of autism in humans, and understanding the stalling and reactivation mechanism could reveal new approaches to therapies. Here, we demonstrate that UPF1, known to stall peptide release during nonsense-mediated RNA decay, is critical for assembly of stalled polysomes in rat hippocampal neurons derived from embryos of either sex. Moreover, UPF1 and its interaction with the RNA binding protein STAU2 are necessary for proper transport and local translation from a prototypical RNA granule substrate and for mGluR-LTD in hippocampal neurons. These data highlight a new, neuronal role for UPF1, distinct from its RNA decay functions, in regulating transport and/or translation of mRNAs that are critical for synaptic plasticity. The elongation and/or termination steps of mRNA translation are emerging as important control points in mGluR-LTD, a form of synaptic plasticity that is compromised in a severe monogenic form of autism, Fragile X Syndrome. Deciphering the molecular mechanisms controlling this type of plasticity may thus open new therapeutic opportunities. Here, we describe a new role for the ATP-dependent helicase UPF1 and its interaction with the RNA localization protein STAU2 in mediating mGluR-LTD through the regulation of mRNA translation complexes stalled at the level of elongation and/or termination.

Case: A 52-year-old man known for a recent cardiac transplantation presented with 6 weeks of incapacitating left shoulder pain with normal x-rays and CT scans. MRI revealed bone edema of the coracoid and glenoid neck with a supraspinatus abscess. Biopsy of the coracoid demonstrated Aspergillus osteomyelitis of the scapula. Conclusion: Aspergillus osteomyelitis is a rare manifestation of invasive aspergillosis and mostly manifests as spondylodiscitis. In this report, we describe a case of Aspergillus osteomyelitis of the scapula treated with combined antifungal therapy and surgery.