Behavior-modulating function of the Duffy Antigen Receptor for Chemokines (DARC) in mice under homeostatic conditions (44.24)

Abstract

Abstract DARC binds promiscuously many inflammatory chemokines without intracellular signal transduction. It is mainly expressed on endothelial cells of postcapillary venules and on erythrocytes, where it acts as a transendothelial chemokine transporter and as a chemokine sink, respectively. Surprisingly, DARC was also shown to be expressed at high density in the cerebellum of human and mouse brain, but with as yet unknown function. We addressed this question by subjecting C57Bl/6 wildtype and DARC-deficient mice to behavior experiments including Morris water maze-, elevated plus maze-, rotarod- and actometer tests. While the water maze results are ambiguous, elevated plus maze trials show a strong aversion of DARC-/- mice to walk to the end of the open arm, which is consistent with anxiety-like behavior. Moreover, DARC-/- mice show greatly reduced locomotor activity, resulting from episodes of reduced mobility that occur more frequently than in the C57Bl/6 controls (elevated plus maze, actometer). Finally, DARC-/- mice spend a significantly reduced time on the rotarod compared to C57Bl/6 controls, probably indicating impaired cerebellar function. We conclude that DARC modulates brain function. Surprisingly, this appears to be happening under homeostatic conditions, although DARC binds mainly inflammatory chemokines. Since DARC shows no signaling, this effect may be indirectly caused by altered brain chemokine concentrations or may result from as yet unknown DARC signaling pathways.