Restoration of Astrocytic Cannabinoid CB1 Receptor Confers Resistance to Ischemia-Induced Neuronal Apoptosis and Cognitive Decline

Post-stroke cognitive impairment (PSCI) involves delayed hippocampal neurodegeneration remote from the primary infarct, yet the underlying mechanisms remain elusive. Integrating clinical data with a photothrombotic mouse model, we show that delayed cognitive deficits correlate with progressive CA1 neuron attrition despite stable hippocampal perfusion. Multi-omic profiling identified astrocytic cannabinoid receptor 1 (CB1R) as a critical hub driving this pathology. Mechanistically, post-ischemic loss of astrocytic CB1R attenuates cAMP/PKA signaling, derepressing NF-κB and triggering the secretion of neurotoxic complement component C3. This astrocytic C3 engages neuronal C3aR, establishing a maladaptive signaling axis that drives CA1 neuron apoptosis. Restoring astrocytic CB1R or disrupting the downstream NF-κB/C3/C3aR cascade rescues hippocampal integrity and memory. Thus, the astrocytic CB1R→cAMP/PKA→NF‑κB→C3/C3aR axis converts focal ischemia into remote hippocampal degeneration, defining a critical two‑week therapeutic window for PSCI.