0045 Characterization of a novel narcolepsy mouse model with conditional ablation of the orexin neurons

Abstract Introduction Narcolepsy type 1 (NT1) is caused by selective loss of orexinergic neurons. Although narcolepsy typically begins in childhood or adolescence, most mouse models induce the orexin peptides neurons from birth. To generate a model that reflects acquired human NT1, we produced recombinant mice expressing diphtheria toxin receptor (DTR) driven prepro-orexin promoter (orexinDTR mice). We examined whether administration (DTX) to orexinDTR and induced symptoms such as sleep-wake fragmentation cataplexy. In addition, investigated effects an 2 (OX2R)-selective agonist OX-201 on DTX-treated mice. Methods with DTR knocked into locus. neurons, intramuscularly injected DTX heterozygous mice, later counted orexin-A (OX-A) immunoreactive Moreover, collected functional data EEG/EMG recordings during dark period Finally, evaluated symptoms, including sleepiness cataplexy, 6 weeks after injection. Results Within week injection DTX, number OX-A was reduced 1% normal no change making melanin-concentrating hormone. Furthermore, treated developed severe within week, very frequent cataplexy (~100 episodes/night) subsequent weeks. These were substantially dose-dependently improved OX-201. Conclusion OrexinDTR are useful simple for understanding neurobiology evaluating new drugs treat symptoms. As only one allele orexin-DTR required, these also convenient crossing other lines, enabling variety methods study markedly it tool compound unlikely be used patients, further demonstrates potential high efficacy OX2R agonists treating narcolepsy. Support (if any) This work funded Takeda Pharmaceutical Company Limited.