Orexin 2 receptor antagonism sex‐dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice

Background and Purpose Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown. Experimental approach Three 8‐week experiments were conducted with wild‐type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg−1·day−1); or (3) Active phase non‐NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX2) receptor antagonist MK‐1064 (40 mg·kg−1·day−1). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry. Key Results Tau transgene suppression improved tauopathy and hippocampal‐dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX2 receptor antagonism induced only short‐lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau‐ and sex‐dependent disruption of OX2 receptor signalling. Conclusions and Implications Pharmacologically reducing hyperarousal corrects tau‐induced sleep/wake and cognitive deficits. Tauopathy causes sex‐dependent disruptions of OX2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.