Explaining variability in ciclosporin exposure in adult kidney transplant recipients

International audienc

Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour

Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1−/−)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1−/−) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance

Circulating levels of inflammation and the effect on exercise-related changes in bone mass, structure and strength in middle-aged and older men

Chronic, low-grade systematic inflammation has been associated with bone loss and increased fracture risk. We previously reported that exercise improved femoral neck bone mineral density (BMD), geometry and strength and lumbar spine trabecular BMD in middle-aged and older men, but had no effect on markers of inflammation. The aim of this study was to examine the association between basal inflammatory status and the adaptive skeletal responses to exercise. Secondary analysis was completed on 91 men aged 50–79 years who participated in an 18-month program of progressive resistance training plus weight-bearing impact exercise (3 day/week) with and without additional calcium–vitamin D 3 . Markers of inflammation (serum hs-CRP, TNF-α and IL-6) and DXA and QCT-derived BMD, bone structure and strength at the lumbar spine and proximal femur were measured at baseline and 18 months. Multiple regression was used to assess associations between skeletal changes and both baseline levels of individual inflammatory markers and a composite inflammatory index derived from the number of markers categorized into the highest tertile. Baseline serum hs-CRP, TNFα and IL-6 and the composite inflammatory index score were not associated with skeletal changes at any site after adjusting for age, change in lean mass, disease(s)/medication use and adherence to the exercise intervention. In conclusion, this study indicates that basal inflammatory status does not influence the osteogenic response to exercise training in healthy middle-aged and older men. </p

Dopamine–Glutamate Interplay in the Ventral Striatum Modulates Spatial Learning in a Receptor Subtype-Dependent Manner

The ventral striatum (VS) is characterized by a distinctive neural architecture in which multiple corticolimbic glutamatergic (GLUergic) and mesolimbic dopaminergic (DAergic) afferents converge on the same output cell type (the medium-sized spiny neuron, MSN). However, despite the gateway function attributed to VS and its involvement in action selection and spatial navigation, as well as the evidence of physical and functional receptor–receptor interaction between different members of ionotropic GLUergic and DAergic receptors, there is no available knowledge that such reciprocal interaction may be critical in shaping the ability to learn novel spatial and non-spatial arrangement of stimuli. In this study, it was evaluated whether intra-VS bilateral infusion of either N-methyl-D-aspartate (NMDA) or a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-selective antagonists may suppress the ability to detect spatial or non-spatial novelty in a non-associative behavioral task. In a second set of experiments, we further examined the hypothesis that VS-mediated spatial information processing may be subserved by some preferential receptor–receptor interactions among specific GLUergic and DAergic receptor subtypes. This was assessed by concomitant intra-VS infusion of the combination between subthreshold doses of either NMDA or AMPA receptor antagonists with individual D1 or D2 receptor blockade. The results of this study highlighted the fact that NMDA or AMPA receptors are differentially involved in processing of spatial and non-spatial novelty, and showed for the first time that preferential NMDA/D1 and AMPA/D2 receptor–receptor functional communication, but not NMDA/ D2 and AMPA/D1, is required for enabling learning of novel spatial information in the VS

D1 and D2 receptors antagonist injections in the prefrontal cortex selectively impair spatial learning in mice

on line publication 9.8.200