Wake-active brainstem GABA neurons signal sleep pressure by upregulating AMPA receptors to drive recovery sleep 

ABSTRACT

How the brain compensates for sleep deprivation (SD) by generating recovery sleep (RS) is not understood. Using Ca²⁺ photometry, we identified a WAKE/rapid eye movement sleep (REMS)-active somatostatin/parvalbumin GABAergic population in the mouse brainstem oral pontine reticular nucleus (PnO^Vgat). Following SD, PnO^Vgat cells transiently switched for the first hour to higher activity during non-REMS (NREMS), promoting RS. Chemogenetic activation of PnO^Vgat neurons prolonged NREMS, whereas ablation blunted electroencephalogram (EEG) delta power rebound and slowed RS accumulation. During RS, the selective switch of PnO^Vgat cells to having higher Ca²⁺ levels in NREMS correlated with elevated levels of synaptic proteins PSD95, activated calmodulin-dependent kinase II CaMKII (pCaMKII T286), activated PKA (pPKA T197), and GluA1-containing AMPA receptor subunits with enhanced serine phosphorylation. All increases started during SD and persisted after the first hour of RS. Patch-clamp recordings demonstrated increased postsynaptic AMPA/sleep homeostasis (NMDA) receptor ratios in PnO^Vgat cells 1 h after RS, indicating increased excitability and greater capacity to drive RS. In contrast, an intermingled population of GABA/glycinergic neurons did not respond to SD, despite having similar baseline WAKE/REMS activities and an ability to promote NREMS. The PnO also contained an intermingled population of excitatory PnO^Vglut2 WAKE/REMS-active neurons; lesioning them caused hypoactivity, but sleep or WAKE amounts were unaffected. The synaptic homeostasis hypothesis (SHY) proposes that as wakefulness progresses, synaptic AMPA receptor activity is enhanced, and subsequently downregulated during NREMS to rebalance circuit function. We suggest that a variation of SHY implements catching up on lost sleep, with glutamate receptor plasticity in the PnO tracking time awake and adjusting NREMS amounts accordingly.

PMID:42161267 | DOI:10.1016/j.cub.2026.04.059