0418 Effect of Acute Administration of DORA-12 on Sleep Impairment in the Aged PS19 Mouse Model of Tauopathy

Abstract

Abstract Introduction Aged PS19 mice (MAPT P301S), a mouse model of tauopathy and neurodegeneration, display reduced NREM and REM sleep starting around 8-9 months before death around 12 months. Here, we tested the acute effect of a dual orexin receptor antagonist (DORA-12) on sleep in 11 mice (5 male, 6 female) at 10.3±1.8 months. Methods Two consecutive 24-hour recordings (12/12hr L:D cycle) were scored semi-automatically for non-REM sleep, REM sleep, and wake in mice implanted with EEG/EMG. Mice were treated with either vehicle (day 1) or 100mg/kg of DORA-12 (day 2) by oral gavage at both ZT0 and ZT9. Results After the first dose at ZT0, both latency to the first NREM sleep episode (paired t-test p=0.002) and to the first REM sleep episode (paired t-test p=0.005) was significantly shorter with DORA-12 (NREM: 20.8±17.8 min.; REM: 23.5±21.2 min.) compared to vehicle (NREM: 49.2±22.3 min.; REM: 127.0±93.3 min.). There was no difference in NREM or REM sleep latency observed after the second dose at ZT9. DORA-12 treatment increased NREM duration across the 24hr period (DORA-12: 664±52 min.; Veh: 601±54 min., paired t-test p=0.007) and also after the 2nd dose (DORA-12: 311±65 min.; Veh: 263±84 min., paired t-test p=0.009). DORA-12 treatment also increased REM duration across 24hrs (DORA-12: 61±30 min.; Veh: 48±29 min., paired t-test p=0.014) but not after the 2nd dose alone (DORA-12: 22±14 min.; Veh: 20±15 min., paired t-test p=0.388). Notably in both vehicle and DORA-12 conditions, we observed apparent dream enactment behavior including mastication, paw grasp, and fore limb extension during REM in 3 of 11 PS19 mice (all male), not typically observed in younger PS19 or age-matched non-transgenic mice, suggestive of a possible REM behavior disorder (RBD) phenotype. Wake-like behaviors occurred during theta-dominant EEG but with an EMG amplitude >4SD the preceding NREM sleep baseline for at least > 1sec. Conclusion In aged PS19 mice, DORA-12 was found to decrease the latency to NREM and REM after the first dose while also increasing NREM and REM duration across the entire 24hr recording period. We also capture a heretofore undescribed RBD-like phenotype in aged PS19 tauopathy mice. Support Merck MISP