Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2 -/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety-and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses

Response Shift in Parents\u27 Assessment of Health-Related Quality of Life of Children with New-onset Epilepsy

OBJECTIVE: Diagnosis of epilepsy is known to impact health-related quality of life (HRQOL) of children with new-onset epilepsy and can also influence their conceptualization and valuation of HRQOL construct, also known as response shift. This study investigates the presence of response shift in a cohort of children with new-onset epilepsy. METHODS: Data are from the HEalth-Related QUality of Life in children with Epilepsy Study, a prospective cohort study of 373 children with new-onset epilepsy. Hypotheses about the presence of reconceptualization, reprioritization, and recalibration response shift were tested in the Quality of Life in Childhood Epilepsy (QOLCE-55) Questionnaire, a parent-reported, disease-specific HRQOL measure, using Oort\u27s structural equation model between baseline and 1-year follow-up. Model fit was assessed using log-likelihood ratio test, root mean square error of approximation, and comparative fit index. RESULTS: Small positive uniform recalibration response shift effects were observed on physical, emotional, and social functioning domains of the QOLCE-55, but negligibly small negative nonuniform recalibration response shift effect was observed on social functioning domain. There was no significant change in overall QOLCE-55 scores over time after adjusting for response shift effects. SIGNIFICANCE: Parents of children with new-onset epilepsy are likely to positively recalibrate (upward bias) their assessments of their children\u27s HRQOL over a 1-year period after diagnosis. This study highlights the potential benefits of response shift as a desired consequence in parents\u27 perception of changes in HRQOL of children with new-onset epilepsy

Multivariate Trajectories Across Multiple Domains of Health-Related Quality of Life in Children with New-Onset Epilepsy

The diagnosis of epilepsy in children is known to impact the trajectory of their health-related quality of life (HRQOL) over time. However, there is limited knowledge about variations in longitudinal trajectories across multiple domains of HRQOL. This study aims to characterize the heterogeneity in HRQOL trajectories across multiple HRQOL domains and to evaluate predictors of differences among the identified trajectory groups in children with new-onset epilepsy. Data were obtained from the Health Related Quality of Life in Children with Epilepsy Study (HERQULES), a prospective multi-center study of 373 children newly diagnosed with new-onset epilepsy who were followed up over 2years. Child HRQOL and family factors were reported by parents, and clinical characteristics were reported by neurologists. Group-based multi-trajectory modeling was adopted to characterize longitudinal trajectories of HRQOL as measured by the individual domains of cognitive, emotional, physical, and social functioning in the 55-item Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Multinomial logistic regression was used to assess potential factors that explain differences among the identified latent trajectory groups. Three distinct HRQOL trajectory subgroups were identified in children with new-onset epilepsy based on HRQOL scores: High (44.7%), Intermediate (37.0%), and Low (18.3%). While most trajectory groups exhibited increasing scores over time on physical and social domains, both flat and declining trajectories were noted on emotional and cognitive domains. Less severe epilepsy, an absence of cognitive and behavioral problems, lower parental depression scores, better family functioning, and fewer family demands were associated with a Higher or Intermediate HRQOL trajectory. The course of HRQOL over time in children with new-onset epilepsy appears to follow one of three different trajectories. Addressing the clinical and psychosocial determinants identified for each pattern can help clinicians provide more targeted care to these children and their families

Cell-type-specific translational control of spatial working memory by the cap-binding protein 4EHP

Abstract The consolidation of learned information into long-lasting memories requires the strengthening of synaptic connections through de novo protein synthesis. Translation initiation factors play a cardinal role in gating the production of new proteins thereby regulating memory formation. Both positive and negative regulators of translation play a critical role in learning and memory consolidation. The eukaryotic initiation factor 4E (eIF4E) homologous protein (4EHP, encoded by the gene Eif4e2) is a pivotal negative regulator of translation but its role in learning and memory is unknown. To address this gap in knowledge, we generated excitatory (glutamatergic: CaMKIIα-positive) and inhibitory (GABAergic: GAD65-positive) conditional knockout mice for 4EHP, which were analyzed in various behavioral memory tasks. Knockout of 4EHP in Camk2a-expressing neurons (4EHP-cKOexc) did not impact long-term memory in either contextual fear conditioning or Morris water maze tasks. Similarly, long-term contextual fear memory was not altered in Gad2-directed 4EHP knockout mice (4EHP-cKOinh). However, when subjected to a short-term T-maze working memory task, both mouse models exhibited impaired cognition. We therefore tested the hypothesis that de novo protein synthesis plays a direct role in working memory. We discovered that phosphorylation of ribosomal protein S6, a measure of mTORC1 activity, is dramatically reduced in the CA1 hippocampus of 4EHP-cKOexc mice. Consistently, genetic reduction of mTORC1 activity in either excitatory or inhibitory neurons was sufficient to impair working memory. Taken together, these findings indicate that translational control by 4EHP and mTORC1 in both excitatory and inhibitory neurons are necessary for working memory

microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP

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