Mood disorders represent some of the most common and proliferating health problems worldwide. The present knowledge on the molecular regulation and intracellular signalling mechanisms of anxiety and depression behaviour is incomplete. A better understanding and the development of novel, improved therapeutic treatment would fill a medical need. To study the function of signal transduction pathways in the brain requires control of the activity of a signalling protein in a temporal manner in a selected cell type of the brain. Signalling processes undergo cycles of activation and repression, such that their manipulation into both directions is of experimental interest. This project will focus on the development and application of a new inducible and reversible switch to modulate the activity of signalling molecules at the protein level in the postnatal mouse brain, with the MAP Kinase (MAPK) pathway as a case study. This switch relies on the posttranslational activation of hyperactive or dominant negative protein kinase mutants fused with the ERT2 mutant estrogen receptor ligand binding domain. In mice the ERT2 technology is routinely applied to induce the activity of Cre recombinase but is not yet utilised in vivo to manipulate endogenous proteins. Here, B-Raf kinase provides an excellent starting point since the functionality of mutant B-Raf-ERT2 fusion proteins to activate in vitro MAPK signalling is known.
By the use of a dominant negative or hyperactive B-Raf fusion protein the fusion protein technology will be for the first time applied to the inducible enhancement or repression of an endogenous signalling pathway in brain neurons. In these mice MAPK signalling can be manipulated in a cell type specific and temporal manner by a small molecule inducer. In particular, the hypothesis that a transient increase of MAPK signalling in glutamatergic neurons of the pubertal brain, results in increased anxiety and depression-like behaviour of adult mice, will be tested.
Start Date: 2011-01-15 End Date: 2013-01-14 EU Contribution: 162 161 Euro Total Costs: 162 161 Euro Programme Acronym: FP7-People Subprogramme Area: FP7-PEOPLE-2009-IEF Marie Curie: "Promoting science"