The cellular prion protein PrPc is a glycosylphosphatidylinositol-anchored cell-surface protein whose biological function is unclear. We used the murine 1C11 neuronal differentiation model to search for PrPc-dependent signal transduction through antibody-mediated cross-linking. A caveolin-1-dependent coupling of PrPc to the tyrosine kinase Fyn was observed. Clathrin might also contribute to this coupling. The ability of the 1C11 cell line to trigger PrPc-dependent Fyn activation was restricted to its fully differentiated serotonergic or noradrenergic progenies. Moreover, the signaling activity of PrPc occurred mainly at neurites. Thus, PrPc may be a signal transduction protein.

The extent to which microbiota alterations define or influence the outcome of metabolic diseases is still unclear, but the byproducts of microbiota metabolism are known to have an important role in mediating the host-microbiota interaction. Here, we identify that in both pre-clinical and clinical settings, metabolic syndrome is associated with the reduced capacity of the microbiota to metabolize tryptophan into derivatives that are able to activate the aryl hydrocarbon receptor. This alteration is not merely an effect of the disease as supplementation with AhR agonist or a Lactobacillus strain, with a high AhR ligand-production capacity, leads to improvement of both dietary- and genetic-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis, through improvement of intestinal barrier function and secretion of the incretin hormone GLP-1. These results highlight the role of gut microbiota-derived metabolites as a biomarker and as a basis for novel preventative or therapeutic interventions for metabolic disorders.

The serotonin transporter (SERT) ensures the recapture of serotonin and is the pharmacological target of selective serotonin reuptake inhibitor (SSRI) antidepressants. We show that SERT is a target of microRNA-16 (miR-16). miR-16 is expressed at higher levels in noradrenergic than in serotonergic cells; its reduction in noradrenergic neurons causes de novo SERT expression. In mice, chronic treatment with the SSRI fluoxetine (Prozac) increases miR-16 levels in serotonergic raphe nuclei, which reduces SERT expression. Further, raphe exposed to fluoxetine release the neurotrophic factor S100β, which acts on noradrenergic cells of the locus coeruleus. By decreasing miR-16, S100β turns on the expression of serotonergic functions in noradrenergic neurons. Based on pharmacological and behavioral data, we propose that miR-16 contributes to the therapeutic action of SSRI antidepressants in monoaminergic neurons.