Abstract
Sleep homeostasis is a core mechanisms of sleep regulation. However, molecular substrates that modulate neuronal activity and plasticity during this process remains elusive. Homeostatic scaling mechanisms ensure stable net firing of neurons. Nevertheless, the involvement of scaling regulators in sleep homeostasis is unknown. By using Crispr/Cas9-mediated somatic knockouts, gene overexpression and monitoring of neuronal activity, we showed that the GWAS-identified insomnia and schizophrenia risk gene Fxr1 is engaged by scaling and sleep deprivation to controls AMPA receptors and synaptic strength. Regulation of Fxr1 under these conditions requires GSK3β. Furthermore, translatome sequencing revealed the engagement of local protein synthesis and synaptic structure associated transcripts by Fxr1 during sleep deprivation. Fxr1 may thus represent a molecular link between mental illnesses, homeostatic synaptic plasticity and sleep homeostasis.
One Sentence Summary Homeostatic upscaling and sleep homeostasis engage a common regulator