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Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 kinase 1(More)
Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, fragile X mental retardation protein (FMRP), an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout mice, the(More)
Tuberous sclerosis complex (TSC) and fragile X syndrome (FXS) are caused by mutations in negative regulators of translation. FXS model mice exhibit enhanced metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). Therefore, we hypothesized that a mouse model of TSC, ΔRG transgenic mice, also would exhibit enhanced mGluR-LTD. We measured(More)
The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly(More)
The proper regulation of translation is required for the expression of long-lasting synaptic plasticity. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 α (eIF2α) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To determine the role of PERK in hippocampal synaptic plasticity, we used the Cre-lox(More)
Brain-derived neurotrophic factor (BDNF) plays an important role in neurodevelopment, synaptic plasticity, learning and memory, and in preventing neurodegeneration. Despite decades of investigations into downstream signaling cascades and changes in cellular processes, the mechanisms of how BDNF reshapes circuits in vivo remain unclear. This informational(More)
Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1. However, small molecule inhibitors of S6K1 could(More)
Stimulus-triggered protein synthesis is critical for brain health and function. However, due to technical hurdles, de novo neuronal translation is predominantly studied in cultured cells, whereas electrophysiological and circuit analyses often are performed in brain slices. The different properties of these two experimental systems create an information gap(More)
Persons with pervasive developmental disorders (PDD) exhibit a range of cognitive deficits that hamper their quality of life, including difficulties involving communication, sociability, and perspective-taking. In recent years, a variety of studies in mice that model genetic syndromes with a high risk of PDD have provided insights into the underlying(More)