1. Bhattacharya A, Mamcarz M, Mullins C, Choudhury A, Boyle RG, Smith DG, Walker DW, Klann E. {{Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice}}. {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}. 2015 Dec 28.
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 potentially ameliorate pathological phenotypes of diseases which are based on aberrant translation and protein expression. One such condition is Fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorders (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macro-orchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling.Neuropsychopharmacology accepted article preview online, 28 December 2015. doi:10.1038/npp.2015.369.
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2. Bora E, Pantelis C. {{Meta-analysis of social cognition in attention-deficit/hyperactivity disorder (ADHD): comparison with healthy controls and autistic spectrum disorder}}. {Psychological medicine}. 2015 Dec 28:1-18.
BACKGROUND: Impairment in social cognition is an established finding in autism spectrum disorders (ASD). Emerging evidence suggests that attention-deficit/hyperactivity disorder (ADHD) might be also associated with deficits in theory of mind (ToM) and emotion recognition. However, there are inconsistent findings, and it has been debatable whether such deficits persist beyond childhood and how similar social cognitive deficits are in ADHD v. ASD. METHOD: We conducted a meta-analysis of social cognition, including emotion recognition and ToM, studies in ADHD compared with healthy controls and ASD. The current meta-analysis involved 44 studies comparing ADHD (n = 1999) with healthy controls (n = 1725) and 17 studies comparing ADHD (n = 772) with ASD (n = 710). RESULTS: Facial and vocal emotion recognition (d = 0.40-0.44) and ToM (d = 0.43) abilities were significantly impaired in ADHD. The most robust facial emotion recognition deficits were evident in anger and fear. Social cognitive deficits were either very subtle (emotion recognition) or non-significant (ToM) in adults with ADHD. Deficits in social cognition, especially ToM, were significantly more pronounced in ASD compared with ADHD. General cognitive impairment has contributed to social cognitive deficits in ADHD. CONCLUSIONS: Performance of individuals with ADHD on social cognition lies intermediate between ASD and healthy controls. However, developmental trajectories of social cognition probably differ between ADHD and ASD as social cognitive deficits in ADHD might be improving with age in most individuals. There is a need for studies investigating a potential subtype of ADHD with persistent social cognitive deficits and exploring longitudinal changes in social cognition during development.
