ß-arrestins and neurogenesis in Treatment Resistant Depression. – DEP-ARREST
Major depressive disorders (MDD) are highly prevalent and disabiliting conditions, associated with significant mortality, and extraordinary costs for the society.
Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin and Noradrenalin Reuptake Inhibitors (SNRI) are the most commonly prescribed antidepressant drugs for MDD. But, 60% of major depressive episodes (MDE) do not respond adequately and 20-30% are resistant to SSRI/SNRI, defining treatment resistant depression (TRD). To date, the mechanisms, biomarkers and biological predictors, moderators and mediators of non-response and resistance to SSRI/SNRI remain poorly known.
?eta-arrestins are key regulators and scaffolds for G-protein-coupled receptor (GPCR) signaling. They act as molecular scaffolds that recruit signaling molecules, such as the protein kinase B (Akt) (involved in cell survival and proliferation), the extracellular-regulated kinase (Erk) (involved in cell proliferation, differentiation and survival) and the Glycogen Synthase Kinase-3ß (GSK-3ß) (involved in neuronal cell development). ß-arrestins can regulate the Akt/GSK3 complex and densensitize GPCR including serotonin and dopamine receptors. Thus ß-arrestins are major candidate molecules for the regulation of antidepressant behavioral effects and for the regulation of adult neurogenesis, neurogenesis being potentially involved in behavioral response to antidepressants. Indeed, recent animal studies show that neurogenesis within the hippocampus mediates, at least in part, the antidepressant effects of SSRI. Interestingly, adult neurogenesis in the olfactory system is also impaired in animal models of depression, suggesting that the olfactory deficits described in MDD may also be related to altered olfactory bulb neurogenesis. Thus, the ß-arrestins signaling pathway is suspected to be involved both in antidepressant response and adult neurogenesis.
Our hypotheses are that 1) non-response/resistance to SSRI/SNRI in MDD depend on the ß-arrestin signaling pathway and that impairments of some elements of this pathway may impair antidepressant response; 2) the association between the ß-arrestin signaling pathway and non-response/resistance to antidepressants is mediated by impaired adult neurogenesis.
Thus, the impact of the ß-arrestin signaling pathway will be assessed on antidepressant non-response / resistance and neurogenesis (hippocampus and olfactory bulbs), in both mice and MDD patients, looking for predictors, moderators and mediators of non-response / resistance to antidepressant drugs within the ß-arrestin signaling pathway.
The methodology of this project is based on a translational approach and several levels of analysis and tools such as genotypes, brain and blood expression of ß-arrestins and their signaling cascade elements. Indeed, data generated with the CORT model, a new animal model of depression of our group, will be tested in the already available METADAP cohort, also coordonated by our group, a large french cohort of 600 depressed patients and in a de novo study of TRD.
The results expected are: 1) Blunted expression of the ß-arrestin signaling pathway predicts non-response and resistance to SSRI/SNRI; 2) Changes in the functional status of molecular components involved in the ß-arrestin signaling pathway (increased Akt/Erk activation/GSK-3ß inactivation) predict non-response and resistance to SSRI/SNRI; 3) Blunted expression of the ß-arrestins pathway prevents the effects of antidepressants on adult neurogenesis in the hippocampus and olfactory system.
The ultimate goal of this proposal is, not only to better understand the mechanisms of action of SSRI/SNRI in MDD and to propose new mechanisms of action for new antidepressant drugs which could be indicated in the treatment of TRD, but also to improve antidepressant treatment of depressed patients, by identifying markers and predictors of non-response or resistance to antidepressants, within the ß-arrestin-dependent signaling pathway.
Madame Emmanuelle CORRUBLE (INSERM Unité 669) – firstname.lastname@example.org
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM Unité 669
PSUD Université Paris-Sud - EA3544
Unité Perception et Mémoire
Help of the ANR 590,578 euros
Beginning and duration of the scientific project: March 2012 - 36 Months