Pathophysiology of Narcolepsy

The sleep-wake switch is a useful way of summarizing how the wakefulness- and sleep-promoting systems interact to ensure stable sleep and wake states.1

The sleep-wake switch is a useful way of summarizing how the wakefulness- and sleep-promoting systems interact to ensure stable sleep and wake states.1

Animation reprinted by permission from Macmillan Publishers Ltd: Nature. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.

In patients with narcolepsy type 1, the loss of the stabilizing influence of hypocretin can lead to a decrease in activating neurotransmitters and associated reduction in cortical activation and wakefulness during the day and increased daytime sleepiness.2,3 Sleep disruption in narcolepsy may reflect the loss of the stabilizing influence on the sleep-wake switch, leading to unwanted transitions between wake and sleep.1,2

 
Animation reprinted by permission from Macmillan Publishers Ltd: Nature. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.

The sleep-wake switch is composed of wake-active neurons and associated neurotransmitters, such as acetylcholine, dopamine, histamine, norepinephrine, and serotonin; sleep-active neurons and the associated neurotransmitter gamma-aminobutyric acid (GABA); and the stabilizing neuromodulator hypocretin.1-3

 
During wakefulness, activating monoaminergic wake-promoting neurons and their associated wake-promoting neurotransmitters promote wakefulness by activating the cerebral cortex and by inhibiting the sleep-promoting neurons. Some wake-promoting neurotransmitters, such as serotonin and norepinephrine, inhibit REM sleep and help maintain motor control during wakefulness.1-3 In individuals with normal wakefulness, hypocretin is thought to stabilize wakefulness during the day, both by activating the cerebral cortex and by stimulating the wake-promoting systems to increase wake-promoting neurotransmitter activity.1-3 Hypocretin also inhibits REM sleep and activates the wake-promoting neurons that inhibit REM sleep and help sustain muscle tone during wakefulness.2,3 One of the roles of hypocretin, therefore, is to promote wakefulness and inhibit REM sleep during the day, by reinforcing monoaminergic activation.2,3
Sleep-promoting neurons, which contain the inhibitory neurotransmitter GABA, are thought to promote sleep by inhibiting wake-promoting neurons, including those making hypocretin. Sleep is maintained by the inhibition of the hypocretin and monoaminergic neurons, which prevents an increase in wake-promoting activity that might interrupt sleep.1,3
Narcolepsy type 1 is caused by hypocretin deficiency, thought to be due to a selective loss of hypothalamic hypocretin-producing neurons.2-5 Narcolepsy type 2 is a type of narcolepsy that is most likely heterogeneous. A subgroup of about one-fourth to one-third of patients with narcolepsy type 2 will have hypocretin deficiency.4,6,7 The underlying pathophysiology of the remainder of patients who have normal CSF hypocretin-1 levels is unknown.4
 
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Neurobiology of Normal Wakefulness

During wakefulness, activating monoaminergic wake-promoting neurons and their associated wake-promoting neurotransmitters promote wakefulness by activating the cerebral cortex and by inhibiting the sleep-promoting neurons. Some wake-promoting neurotransmitters, such as serotonin and norepinephrine, inhibit REM sleep and help maintain motor control during wakefulness.1-3 In individuals with normal wakefulness, hypocretin is thought to stabilize wakefulness during the day, both by activating the cerebral cortex and by stimulating the wake-promoting systems to increase wake-promoting neurotransmitter activity.1-3 Hypocretin also inhibits REM sleep and activates the wake-promoting neurons that inhibit REM sleep and help sustain muscle tone during wakefulness.2,3 One of the roles of hypocretin, therefore, is to promote wakefulness and inhibit REM sleep during the day, by reinforcing monoaminergic activation.2,3

Neurobiology of Normal Sleep

Sleep-promoting neurons, which contain the inhibitory neurotransmitter GABA, are thought to promote sleep by inhibiting wake-promoting neurons, including those making hypocretin. Sleep is maintained by the inhibition of the hypocretin and monoaminergic neurons, which prevents an increase in wake-promoting activity that might interrupt sleep.1,3

Neurobiology of Narcolepsy

Narcolepsy type 1 is caused by hypocretin deficiency, thought to be due to a selective loss of hypothalamic hypocretin-producing neurons.2-5 Narcolepsy type 2 is a type of narcolepsy that is most likely heterogeneous. A subgroup of about one-fourth to one-third of patients with narcolepsy type 2 will have hypocretin deficiency.4,6,7 The underlying pathophysiology of the remainder of patients who have normal CSF hypocretin-1 levels is unknown.4

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