Homer1a drives homeostatic scaling-down of excitatory synapses during sleep.
Sleep is an essential process that supports learning and memory by acting on synapses through poorly understood molecular mechanisms. Using biochemistry, proteomics, and imaging in mice, we find that during sleep, synapses undergo widespread alterations in composition and signaling, including weakening of synapses through removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors mGluR1/5. Homer1a serves as a molecular integrator of arousal and sleep need via the wake- and sleep-promoting neuromodulators, noradrenaline and adenosine, respectively. Our data suggest that homeostatic scaling-down, a global form of synaptic plasticity, is active during sleep to remodel synapses and participates in the consolidation of contextual memory.
Solomon Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA.
Graham H
GH
Diering
Department of Biological Chemistry, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
Raja S
RS
Nirujogi
Solomon Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA.
Richard H
RH
Roth
Solomon Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA.
Paul F
PF
Worley
Department of Biological Chemistry, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
Akhilesh
A
Pandey
Solomon Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA. rhuganir@jhmi.edu.
Richard L
RL
Huganir
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D003071:Cognition / Q000502:physiology; D006706:Homeostasis; D000072233:Homer Scaffolding Proteins / Q000235:genetics / Q000502:physiology*; D007858:Learning / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D009638:Norepinephrine / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*
C578936:Grm5 protein, mouse; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D000241:Adenosine; D009638:Norepinephrine