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Fragile X mental retardation protein promotes translation, contrary to its assumed function Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability and autism ( 1 ). FXS is usually caused by transcriptional silencing of the fragile X mental retardation 1 ( FMR1 ) gene, which encodes fragile X mental retardation protein (FMRP), an RNA-binding protein that is thought to repress the translation of specific messenger RNAs (mRNAs). Precise translational control is especially critical in neurons because rapid synthesis of proteins from preexisting mRNAs underlies many forms of synaptic plasticity, which is altered in animal models of FXS ( 2 ). Progress has been made in identifying RNAs that FMRP binds, but its functional targets and modes of translational control remain elusive, especially during development ( 3 – 7 ). On page 709 of this issue, Greenblatt and Spradling ( 8 ) use Drosophila melanogaster oocytes to demonstrate that FMRP increases the translation of multiple long mRNAs, many of which are implicated in intellectual disability and autism.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2α in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2α phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.

Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS. Elevated protein synthesis, and dysregulated mGluR signalling, are documented in fragile X syndrome (FXS) Here the authors use proteomic analysis in a mouse model of FXS, and following mGluR5 stimulation, to identify potential biomarkers for the disease.

Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. To determine the neurobiological functions of AKAP11, we conduct multi-omic and neurobiological analyses of Akap11 mutant mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose loss leads to dramatically increased levels of PKA subunits and phosphorylated PKA substrates, especially in synapses. Akap11 mutant mice show extensive transcriptomic changes throughout the brain, including prominent decreases in synapse-related genes sets. Gene expression is highly impacted in spiny projection neurons of the striatum, a brain region implicated in motivation, cognition and psychotic disorders. Real-time measurements of PKA activity reveal elevated basal PKA activity in the striatum of Akap11 -/- mice, with exaggerated additional response to dopamine receptor antagonists. Behaviorally, Akap11 mutant mice show abnormally prolonged locomotor response to amphetamine, deficits in associative learning and contextual discrimination, as well as depression-like behaviors. Our study connects molecular changes to circuit dysfunction and behavioral disturbance in a genetically valid animal model of psychotic disorder. Here authors show loss of AKAP11 , a strong genetic risk factor for bipolar disorder and schizophrenia, disrupts PKA proteostasis and signaling, leading to widespread transcriptomic alterations across the brain, particularly in striatal neurons, as well as altered behavior.

Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes ( Akap11 , Dagla , Gria3 , Grin2a , Sp4 , Srrm2 , Zmym2 ). While all studied brain regions were affected, the striatum and the thalamus emerged as key brain regions of convergence. Striatum showed downregulation of synapse- and oxidative phosphorylation-related gene sets in all models. In the thalamus, mutants separated into two groups based on transcriptomic phenotype: synapse-related gene sets were upregulated in mutants with only schizophrenia and bipolar association, and were downregulated in mutants that are associated with developmental delay/intellectual disability in addition to schizophrenia. Overall, our meta-analysis reveals convergence and divergence in brain transcriptomic phenotype in these schizophrenia genetic models, supports the involvement of striatal disturbance and synapse dysfunction in schizophrenia, and points to a key role of the thalamus.

Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets andmodes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene specificity of altered messenger RNA (mRNA) translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA sequencing on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint (RF) abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in RF abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the leading inherited form of intellectual disability. FMRP is widely thought to repress de novo protein synthesis, but its translational targets and modes of control remain in dispute. Our laboratory has previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis, as well as synaptic and behavioral phenotypes in FXS mice. To examine the gene-specificity of the alteration in protein synthesis in FXS and the mechanism of rescue with genetic reduction of S6K1, I carried out ribosome profiling and RNA-Seq on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. First, I observed reduced ribosome footprint (RF) abundance in the majority of differentially translated genes in the cortices of FXS mice. Second, I used novel molecular assays to discover evidence that the reduction in RF abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state and is normalized by inhibition of S6K1. Third, I found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Fourth, examination of ribosome-bound mRNA of dopamine D1 receptor-expressing striatal neurons in FXS mice using an orthogonal assay (TRAP-Seq) revealed highly concordant alterations in de novo protein synthesis, suggesting a conserved molecular mechanism for FXS. My findings reveal the global and gene-specific aberrations in mRNA translation in FXS, a model for FMRP function, and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

Numerous optical-imaging and machine-vision based inspection methods are found that aim to replace visual and human-based inspection with an automated or a highly efficient procedure. However, these machine-vision systems have not been entirely endorsed by civil engineers towards deploying these techniques in practice, partially due to their poor performance in object detection when structural cracks coexist with other complex scenes. A mobile hyperspectral imaging system is developed in this work, which captures hundreds of spectral reflectance values at a pixel in the visible and near-infrared (VNIR) portion of the electromagnetic spectrum bands. To prove its potential in discriminating complex objects, a machine learning methodology is developed with classification models that are characterized by four different feature extraction processes. Experimental validation with quantitative measures proves that hyperspectral pixels, when used conjunctly with dimensionality reduction, possess outstanding potential in recognizing eight different structural surface objects including cracks for concrete and asphalt surfaces, and outperform the gray-values that characterize the texture/shape of the objects. The authors envision the advent of computational hyperspectral imaging for automating structural damage inspection, especially when dealing with complex structural scenes in practice.

Complex neuronal circuit functions emerge from local, actively regulated synaptic protein levels that interplay with synaptic neurotransmission across heterogenous synapse populations. Understanding the mechanisms by which chemical and disease-associated genetic perturbations impact neuronal circuit functions requires simultaneous measurement of these factors with single-synapse resolution at population scale. Here, we combine in situ multimodal imaging of local mRNA translation, synaptic multiprotein composition, and synapse activity measured via calcium or glutamate fluxes, within the same spatially resolved synapses. We apply this approach of multimodal synapse profiling to study ketamine plasticity. Results map a causal network of NR2A-depletion-induced changes to synaptic scaffolding and receptor proteins, driven by synaptic activity and local mRNA translation, which translates to models of schizophrenia and . Thus, multimodal synaptomics can reveal mechanistic neurobiology that underlies chemical and genetic perturbations within the context of scalable neuronal cultures, which can serve as models for human disease and therapeutic development.