Homer1a and mGluR1/5 Signaling in Homeostatic Sleep Drive and Output.

Sleep is an essential physiological behavior that promotes cognitive development and function. Although the switch between sleep/wake cycles is controlled by specific neural circuits, sleep need and the restorative benefits of sleep are likely controlled by cellular mechanisms localized in critical areas of the brain involved in learning and memory including the cortex and hippocampus. However, the molecular basis for the restorative function(s) of sleep that support cognition, or for the homeostatic build-up of sleep need are poorly understood. Synapses undergo local and global changes in strength to support learning and memory and are likely a point of restoration during sleep. Homer1a and mGluR1/5, recently implicated in sleep function, are molecules involved in the scaling down process that weakens synapses during sleep to restore synapse homeostasis. During wake, long-form Homer proteins tether mGluR1/5 to IP3R and to the post-synaptic density (PSD). During sleep, short-form Homer1a uncouples mGluR1/5 from IP3R leaving mGluR1/5 open to interact with other effectors, switching mGluR1/5 signaling from "awake-type" to "sleep-type" signaling modes. Importantly, mGluR1/5 have been implicated in several neurological and neurodevelopmental disorders such as Alzheimer's disease (AD) and autism spectrum disorder (ASD), all of which show abnormal sleep phenotypes, linking sleep, disease, and mGluR1/5 signaling. Further investigation into the downstream effectors of mGluR1/5 and sleep/wake signaling will lead to more targeted therapeutic interventions.