Memory consolidation deficits arise from CB1R-mediated structural-functional decoupling in inhibitory circuits

Rapid eye movement sleep deprivation (RSD) impairs hippocampus-dependent memory consolidation, yet the underlying circuit mechanisms remain elusive. Here, we demonstrate that RSD-induced cognitive deficits are driven by a dual-layered pathological remodeling of hippocampal CA1 inhibitory circuits mediated by cannabinoid receptor 1 (CB1R). First, RSD-evoked CB1R signaling promotes a compensatory but maladaptive increase in inhibitory synapse density, causing a rigid shift in the E/I balance toward excessive static inhibition. Second, through a dynamic systems lens, we reveal that these structural changes are coupled with a systemic deterioration in synaptic quality, characterized by exhaustive release kinetics. Specifically, RSD-activated CB1Rs pathologically expand the readily releasable pool (RRP), triggering an excessive initial burst that precipitates rapid neurotransmitter depletion. Consequently, while the circuit appears over-inhibited at rest, it suffers from dynamic output collapse under high-frequency physiological demands due to this unsustainable release mode. This CB1R-dependent "static over-inhibition but dynamic fragility" erodes circuit resilience and destabilizes memory processing. Our findings identify CB1R-driven suboptimal inhibitory remodeling as a key mechanistic origin of circuit instability following sleep loss.