Sleep need driven oscillation of glutamatergic synaptic phenotype.

The response to sleep loss shows an overall increase in synaptic strength and number of cortical, glutamate, AMPA receptor (AMPAR) synapses 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 number of silent synapses are decreased, decreasing the plastic potential to convert silent NMDA to active AMPA synapses. All aspects recover with sleep. The DEGs are enriched for synaptic shaping cellular components (SSCs) controlling 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 that regulates an oscillation of glutamate-synaptic phenotypes facilitating motor learning and training, and if dysfunctional, increases risk for autism.