Oligodendrocyte prosaposin restores subarachnoid haemorrhage-induced consciousness impairment.

Subarachnoid haemorrhage (SAH) is a life-threatening cerebrovascular event frequently accompanied by consciousness disturbances, yet the underlying mechanisms remain poorly defined. Here, we identify oligodendrocytic prosaposin (PSAP) as a critical regulator of thalamocortical connectivity and consciousness following SAH. Using multimodal approaches, including electroencephalogram and electromyogram recordings, optogenetics, single-nucleus RNA sequencing, patch-clamp recording, and magnetic resonance imaging, we demonstrate that SAH disrupts the central lateral thalamus to medial prefrontal cortex pathway via Psap downregulation in oligodendrocytes, leading to impaired PSAP-GPR37 interactions, myelin damage and functional connectivity loss. Psap overexpression or recombinant human PSAP administration restored PSAP-GPR37 interactions, preserved myelin structure and rescued central lateral thalamus to medial prefrontal cortex connectivity after SAH, resulting in improved consciousness and spatial memory. Our findings highlight oligodendrocyte dysfunction as a key mechanism underlying SAH-induced disorders of consciousness and identify PSAP as a potential therapeutic target.