A screen for stress-induced sleep genes in Caenorhabditis elegans reveals a role for glutamate signaling

Sleep is an essential behavioral state that evolved early in animals, possibly with the advent of the nervous system. The complexity of sleep neural networks varies significantly across phylogeny, yet common signaling molecules exist. Stress-induced sleep (SIS) of Caenorhabditis elegans is controlled by 2 sleep interneurons (ALA and RIS), within a 302-celled nervous system. Even in this simple framework, a complex array of signaling molecules is expressed. Here, we surveyed some of these genes for roles in SIS. These included neuropeptides, G-protein coupled receptors, a 2-pored potassium channel, and glutamate signaling components. We found that multiple genes are required for sleep maintenance (i.e. amounts) and/or the precise timing of sleep initiation. In particular, we identified an important role for glutamate signaling. The conserved ionotropic glutamate receptor glr-5 regulates sleep maintenance and timing and is required in a 3-celled circuit of interneurons connected by gap junctions and chemical synapses with RIS. This work suggests that numerous redundant and/or parallel mechanisms have evolved to modulate a simple sleep-regulating circuit in C. elegans, and we speculate that conserved pathways may play similar roles in animals with more complex systems.