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Review
. 2019 Mar 25;92(1):93-101.
eCollection 2019 Mar.

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

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Free PMC article
Review

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

Shenée C Martin et al. Yale J Biol Med. .
Free PMC article

Abstract

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.

Keywords: Alzheimer’s disease; autism; glutamate receptors; immediate early gene; memory; sleep; synapse; synaptic plasticity.

Figures

Figure 1
Figure 1
The sleep homeostasis hypothesis (SHY). SHY predicts that synapses undergo a net increase in strength during wake, through LTP-type mechanisms. Synapse strength is restored to baseline during sleep by selective homeostatic scaling-down.
Figure 2
Figure 2
mGluR1/5 switch between wake and sleep-type signaling gated by Homer1a. Homer scaffold proteins include long forms that contain an EVH domain and coiled-coil domain that allows for the formation of a multivalent tetramer, and an activity-dependent short form, Homer1a, that contains only the EVH domain. During wake, long-form Homer couples mGluR1/5 to Shank scaffold proteins within the PSD and to IP3Rs in the endoplasmic reticulum. Homer1a targeting to the PSD is suppressed during wake by arousal-promoting noradrenaline. At the onset of sleep, drops in noradrenaline and increased levels of adenosine promote Homer1a targeting to synapses, where Homer1a acts as a dominant-negative to uncouple mGluR1/5-IP3R complex. Homer1a also promote agonist independent constitutive signaling of mGluR1/5. We propose a model in which mGluR1/5 switch between awake-type and sleep-type signaling gated by Homer1a.

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