The MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinase) pathway is a cardinal regulator of synaptic plasticity, learning, and memory in the hippocampus. One of major endpoints of this signaling cascade is the 5′ mRNA cap binding protein eIF4E (eukaryotic Initiation Factor 4E), which is phosphorylated on Ser 209 by MNK (MAPK-interacting protein kinases) and controls mRNA translation. The precise role of phospho-eIF4E in the brain is yet to be determined. Herein, we demonstrate that ablation of eIF4E phosphorylation in male mice (4Ekimice) does not impair long-term spatial or contextual fear memory, or the late phase of LTP. Using unbiased translational profiling in mouse brain, we show that phospho-eIF4E differentially regulates the translation of a subset of mRNAs linked to inflammation, the extracellular matrix, pituitary hormones, and the serotonin pathway. Consequently,4Ekimale mice display exaggerated inflammatory responses and reduced levels of serotonin, concomitant with depression and anxiety-like behaviors. Remarkably, eIF4E phosphorylation is required for the chronic antidepressant action of the selective serotonin reuptake inhibitor fluoxetine. Finally, we propose a novel phospho-eIF4E-dependent translational control mechanism in the brain, via the GAIT complex (gamma IFN activated inhibitor of translation). In summary, our work proposes a novel translational control mechanism involved in the regulation of inflammation and depression, which could be exploited to design novel therapeutics.SIGNIFICANCE STATEMENTWe demonstrate that downstream of the MAPK (mitogen-activated protein kinase) pathway, eukaryotic Initiation Factor 4E (eIF4E) Ser209 phosphorylation is not required for classical forms of hippocampal LTP and memory. We reveal a novel role for eIF4E phosphorylation in inflammatory responses and depression-like behaviors. eIF4E phosphorylation is required for the chronic action of antidepressants, such as fluoxetine in mice. These phenotypes are accompanied by selective translation of extracellular matrix, pituitary hormones, and serotonin pathway genes, in eIF4E phospho-mutant mice. We also describe a previously unidentified translational control mechanism in the brain, whereby eIF4E phosphorylation is required for inhibiting the translation of gamma IFN activated inhibitor of translation element-containing mRNAs. These findings can be used to design novel therapeutics for depression.

Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

A mouse model for the fragile X syndrome, the most common form of inherited mental retardation, was generated a number of years ago. It shows characteristics compatible with the clinical symptoms of human patients. These include pathological changes such as macroorchidism, behavioral problems, and diminished visuo-spatial abilities. To investigate whether the fragile X syndrome is a potentially correctable disorder, several groups attempted to rescue the knockout mutation by introduction of an intact copy of the FMR1 gene in the knockout mouse. Two different types of rescue mice have been created by injection of constructs based on FMR1 cDNA or on FMR1 genomic DNA. Several pathological, behavioral and cognitive function tests were performed on these two different rescue mouse lines to compare their characteristics with those of the knockout and control littermates. Each rescue line resembled the control in some aspects though neither of the 2 lines was a full rescue, e.g. resemble the control in all aspects investigated. Thus, rescue of some aspects of the phenotype has been achieved by introduction of FMR1 constructs in the fragile X knockout mice. The results implicate that, even if FMR1 production is cell type specific, the quantity of the FMRP expression is highly critical as overproduction may have a harmful effect.

Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder engendered by transcriptional silencing of the fragile X messenger ribonucleoprotein 1 ( FMR1 ) gene. Given the early onset of behavioral and molecular changes, it is imperative to know the optimal timing for therapeutic intervention. Case reports documented benefits of metformin treatment in FXS children between 2 and 14 y old. In this study, we administered metformin from birth to Fmr1 ^−/y mice which corrected up-regulated mitogen-2 activated protein kinase/extracellular signal-regulated kinase and mammalian/mechanistic target of rapamycin complex 1 signaling pathways and specific synaptic mRNA-binding targets of FMRP. Metformin rescued increased number of calls in ultrasonic vocalization and repetitive behavior in Fmr1 ^−/y mice. Our findings demonstrate that in mice, early-in-life metformin intervention is effective in treating FXS pathophysiology.

Autism spectrum disorder (ASD) is a neurobiologically complex condition with a heterogeneous genetic etiology. Clinically, ASD is diagnosed by social ... Jove

Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder associated with autism spectrum disorder and intellectual disability, is caused by either deletions in human chromosome 22q13 or mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. PMS is highly debilitating, and existing treatments are ineffective. SHANK3 interacts with at least 3 synaptic receptors through synaptic-associated proteins, some of which are upstream of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathways. Metformin, an inhibitor of the mTORC1 and MAPK/ERK signalling pathways, was shown to correct core phenotypes in a fragile X mouse model, offering therapeutic potential for PMS. Male Shank3B^-/-, a PMS mouse model, and wild-type mice were treated from birth with metformin (5 mg/mL) or vehicle. Shank3B^-/- mice displayed increased self-grooming, decreased social interaction, reduced duration and frequency of ultrasonic vocalisations, and impaired hippocampal-dependent memory. Upregulated mTORC1 activity was observed in the hippocampus and prefrontal cortex, along with decreased synaptosomal protein expression in the striatum of GluN2B (an N-methyl-d-aspartate receptor (NMDAR) subunit), Homer1 (a synaptic-associated protein) and GluA2 (an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit), all of which interact with Shank3. Metformin treatment from birth corrected core behavioural impairments, exaggerated mRNA translation, and decreased striatal synaptic protein expression. Considering its exceptional safety profile, metformin is a promising therapeutic option for a rapid clinical translation of PMS treatment.