Sleep need driven oscillation of glutamatergic synaptic phenotype
The response to sleep loss, induced by experimental sleep deprivation (SD), provides insight into the function of sleep. Earlier observations have shown an overall increase in synaptic strength and number of cortical, glutamate, AMPA receptor (AMPAR) synapses in response to SD that is recovered by sleep. However, other aspects of glutamatergic transmission, including NMDA receptor mediated neurotransmission and related upstream synaptic regulators of the glutamate synapse function, have not been well examined. Following SD, we report increased AMPA/NMDA ratio in whole cell recordings of frontal cortical (FC) pyramidal neurons of layers 2-3. Additionally, the ratio of silent/active synapse is decreased after SD reflecting decreased silent synapses and plastic potential to convert silent NMDA to active AMPA synapses. All aspects recover with sleep and are associated with differentially expressed genes (DEGs) affecting glutamatergic synaptic phenotype. The DEGs are enriched for a functional group of synaptic shaping cellular components (SSCs) controling glutamate synapse phenotype, overlap with autism risk genes and are primarily observed in a subtype of excitatory pyramidal neurons that project intra-telencephalically (ExIT neurons). Upstream, sleep-related control is suggested by significant enrichment of genes controlled by transcription factor, MEF2c and nuclear HDAC4, a repressor of MEF2c transcriptional activation. Taken together, we propose a functional role of sleep/wake in FC controlling gene expression, regulating an oscillation of glutamate-synaptic phenotypes that facilitates motor learning and training, and if dysfunctional, increases risk for autism. Overall design: single nuclei RNA-seq on mice with ad-lib sleep and upon sleep deprivation