Abstract
Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency. Cataplexy is classically considered to be an abnormal manifestation of REM sleep and is treated by selective serotonin (5HT) reuptake inhibitors. Here we show that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep. Additionally, double knockout mice showed a significant deficit in the buildup of sleep need. Deleting one allele of the 5HT transporter in hypocretin knockout mice strongly increased EEG theta power during REM sleep and theta and gamma powers during wakefulness. Deleting hypocretin receptors in the dorsal raphe neurons of adult mice did not induce cataplexy but consolidated REM sleep. Our results indicate that cataplexy and REM sleep are regulated by different mechanisms and both states and sleep need are regulated by the hypocretinergic input into 5HT neurons.
Highlights
Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency
We showed that 5HTT deletion in HcrtKO/KO mice leads to a near suppression of cataplexy attacks, without affecting other
In contrast to cataplexy suppression, a large increase in rapid eye movement sleep (REMS) was found in double knockout (DKO) mice, indicating a dissociation between REMS and cataplexy and suggesting that the two states are regulated by different mechanisms, as suggested by Hasegawa et al.[20]
Summary
Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency. We show that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep. Deleting one allele of the 5HT transporter in hypocretin knockout mice strongly increased EEG theta power during REM sleep and theta and gamma powers during wakefulness. Deleting hypocretin receptors in the dorsal raphe neurons of adult mice did not induce cataplexy but consolidated REM sleep. A key wake-promoting system called orexin or hypocretin (hereafter HCRT) is disabled in patients with narcolepsy who presumably lost their HCRT producing neurons[3]. Animal studies established that the HCRT system is critical in sustaining the normal waking state and its genetic defects lead to narcolepsy phenotypes in mice and dogs[10,11]
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