Unbiased genetics identifies a glutamatergic signaling network as a mediator of daily sleep patterns.

Sleep is a fundamental, conserved behavior important for survival. In many species, sleep behavior is controlled by poorly understood interactions between a system of circadian rhythms (CR), which promote sleep at ecologically appropriate times, and a homeostatic sleep drive that accumulates with time awake. The CR is a cellular phenomenon, driven by molecular oscillations of "clock genes" in nearly all cells. Emerging evidence indicates neuronal synapses are a key locus for the accumulation and resolution of sleep need, supporting a cellular basis of sleep need. Indeed, efforts to understand the genetic basis of sleep need identified Homer1a, a regulator of synapse homeostasis. To develop further insight into the genetic basis of sleep regulation, we measured daily sleep patterns in genetically diverse strains of mice from the Collaborative Cross. Strains with 1) highly consolidated light-phase sleep, or 2) fragmented, arrhythmic sleep, were identified for genetic analysis using quantitative trait loci (QTL) mapping. Excitingly, in F2 hybrids, 19 of 32 metrics of sleep and circadian behavior mapped to a narrow QTL containing GRM5, a postsynaptic glutamate receptor and binding partner of Homer1a, and GCPII, an astrocytic enzyme that regulates NAAG, a peptide agonist for the presynaptic/astrocytic glutamate receptor GRM3. Collectively, these genes form a coordinated glutamatergic signaling network across the tri-partite synapse. Pharmacology targeting GRM5, GCPII, and GRM3 strongly modulated sleep, functionally validating them as sleep-regulating genes. Our findings support a model in which synapses act as a cellular site for integration of circadian and sleep-need signals to regulate daily sleep patterns. Significance StatementSleep is a fundamental pillar of human health. Restorative sleep is supported by circadian rhythms (CR). Sleep and CR disruptions are prevalent in neuropsychiatric conditions and are increasingly understood as causal drivers of altered brain function and behavior. Therefore, sleep and CR are attractive therapeutic targets to improve health. However, the basic biological mechanisms that couple our need to sleep with the CR are not understood. Genetic discovery using diverse strains of mice identifies a glutamatergic signaling network coordinated across the synapse as an underlying genetic basis for daily sleep patterns. This work builds upon a growing body showing that excitatory synapses are a cellular site for the resolution of sleep need and interaction with the CR.