PT  - JOURNAL ARTICLE
AU  - Carsten T. Beuckmann
AU  - Christopher M. Sinton
AU  - S. Clay Williams
AU  - James A. Richardson
AU  - Robert E. Hammer
AU  - Takeshi Sakurai
AU  - Masashi Yanagisawa
TI  - Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat
AID  - 10.1523/JNEUROSCI.5560-03.2004
DP  - 2004 May 05
TA  - The Journal of Neuroscience
PG  - 4469--4477
VI  - 24
IP  - 18
4099  - http://www.jneurosci.org/content/24/18/4469.short
4100  - http://www.jneurosci.org/content/24/18/4469.full
SO  - J. Neurosci.2004 May 05; 24
AB  - The sleep disorder narcolepsy has been linked to loss of hypothalamic neurons producing the orexin (hypocretin) neuropeptides. Here, we report the generation of transgenic rats expressing a human ataxin-3 fragment with an elongated polyglutamyl stretch under control of the human prepro-orexin promoter (orexin/ataxin-3 rats). At 17 weeks of age, the transgenic rats exhibited postnatal loss of orexin-positive neurons in the lateral hypothalamus, and orexin-containing projections were essentially undetectable. The loss of orexin production resulted in the expression of a phenotype with fragmented vigilance states, a decreased latency to rapid eye movement (REM) sleep and increased REM sleep time during the dark active phase. Wakefulness time was also reduced during the dark phase, and this effect was concentrated at the photoperiod boundaries. Direct transitions from wakefulness to REM sleep, a defining characteristic of narcolepsy, occurred frequently. Brief episodes of muscle atonia and postural collapse resembling cataplexy were also noted while rats maintained the electroencephalographic characteristics of wakefulness. These findings indicate that the orexin/ataxin-3 transgenic rat could provide a useful model of human narcolepsy.