Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of Fragile X syndrome (FXS). Excess signaling through group 1 metabotropic glutamate receptors is commonly observed in mouse models of FXS, which in part is attributed to dysregulated translation and downstream signaling. Considering the wide spectrum of cellular and physiologic functions that loss of FMRP can affect in general, it may be advantageous to pursue disease mechanism based treatments that directly target translational components or signaling factors that regulate protein synthesis. Various FMRP targets upstream and downstream of the translational machinery are therefore being investigated to further our understanding of the molecular mechanism of RNA and protein synthesis dysregulation in FXS as well as test their potential role as therapeutic interventions to alleviate FXS associated symptoms. In this review, we will broadly discuss recent advancements made towards understanding the role of FMRP in translation regulation, new pre-clinical animal models with FMRP targets located at different levels of the translational and signal transduction pathways for therapeutic intervention as well as future use of stem cells to model FXS associated phenotypes.

Approximately 30 million people currently live with HIV worldwide and the incidence of stress-related disorders, such as post-traumatic stress disorder (PTSD), is elevated among people living with HIV as compared to those living without the virus. PTSD is a severely debilitating, stress-related psychiatric illness associated with trauma exposure. Patients with PTSD experience intrusive and fearful memories as well as flashbacks and nightmares of the traumatic event(s) for much of their lives, may avoid other people, and may be constantly on guard for new negative experiences. This review will delineate the information available to date regarding the comorbidity of PTSD and HIV and discuss the biological mechanisms which may contribute to the co-existence, and potential interaction of, these two disorders. Both HIV and PTSD are linked to altered neurobiology within areas of the brain involved in the startle response and altered function of the hypothalamic-pituitary-adrenal axis. Collectively, the data highlighted suggest that PTSD and HIV are more likely to actively interact than to simply co-exist within the same individual. Multi-faceted interactions between PTSD and HIV have the potential to alter response to treatment for either independent disorder. Therefore, it is of great importance to advance the understanding of the neurobiological substrates that are altered in comorbid PTSD and HIV such that the most efficacious treatments can be administered to improve both mental and physical health and reduce the spread of HIV.

As individuals live longer with HIV, this “graying of the HIV epidemic” has introduced a new set of challenges including a growing number of age and inflammation-related diseases such as cardiovascular disease, type II diabetes, cancer, and dementia. The biological underpinnings of these complex and co-morbid diseases are not fully understood and become very difficult to disentangle in the context of HIV and aging. In the current review we examine the contributions and interactions of HIV, stress, and cognitive impairment and query the extent to which inflammation is the linchpin in these dynamic interactions. Given the inter-relatedness of stress, inflammatory mechanisms, HIV, and cognitive impairment, future work will either need to address multiple dimensions simultaneously or embrace the philosophy that breaking the aberrant cycle at any one point will subsequently remedy the other related systems and processes. Such a single-point intervention may be effective in early disease states, but after perpetuation of an aberrant cycle, adaptations in an attempt to internally resolve the issue will likely lead to the need for multifaceted interventions. Acknowledging that HIV, inflammation, and stress may interact with one another and collectively impact cognitive ability is an important step in fully understanding an individual's complete clinical picture and moving towards personalized medicine.

Summary Genomic studies have repeatedly associated variants in the gene encoding microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1α-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1α and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.

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