Drosophila RSK: A Pivotal Regulator of Circadian Plasticity at the Neuronal and Behavioral Level.

Abstract

Circadian neuronal plasticity describes daily recurring changes at the level of neuronal morphology, connectivity and synaptic processes. Disturbance of these plastic changes could result in inflexibility of an organism to adapt behavior to changing environmental cues. The mitogen activated protein kinases (MAPK)/ERK signaling pathway is involved both in circadian processes and neuronal plasticity. Ribosomal S6 kinases (RSK) act as downstream mediators of ERK signaling with apparently pleiotropic-but sometimes poorly understood- functions in the nervous system. This is illustrated by some major gaps in our understanding of the pathophysiological processes caused by RSK2 mutations in humans that lead to intellectual disabilities. Previous studies described the role of Drosophila RSK as one regulator of the molecular circadian oscillator. Here we could show that RSK kinase activity is required to control another aspect of circadian rhythmicity, the daily remodeling of the dorsal branching pattern of the small ventral lateral neurons (s-LN_v) as the central pacemaker cells. Loss of RSK function resulted in more fasciculated and less branched s-LN_v's in the early morning, which could affect synaptic in- or output connectivity. Increased fasciculation correlated with a reduced number of Bruchpilot sites as a marker for presynapses. Analysis of the expression of the Pigment Dispersing Factor PDF in s-LN_v's, the most important signaling factor between clock neurons, revealed no evidence of changes in RSK mutants. Consistent with unaffected PDF signaling as a major output from the s-LN_v's, RSK mutant flies are rhythmic. Their free-running rhythms show even a significantly higher power than those of the wild-type controls. This robustness is at the expense of flexibility to adapt their activity to variations in light conditions. Together with the known role of RSK in olfactory learning and memory processes our results suggest that RSK is required to maintain experience dependent plasticity.