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

• DOI: 10.1101/2025.05.08.652901
• Publication Date: 2025-05-14T13:10:11Z
• Authors: Sawyer Grizzard; Julia S. Lord; Alicia L. Ravens; Yajing Hao; Wei Tang; Sung Hyun Lee; Sarah Jo Sleiman; Kathryn K. Joyce; Kevin D. Donohue; Bruce F. O’Hara; Fei Zou; Tal Kafri; Graham H. Diering
• Keywords: Mediator; Sleep

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