• DOI:10.1126/scitranslmed.3004685
• Corpus ID: 44236050

Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors

@article{Rye2012ModulationOV,
  title={Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors},
  author={David B. Rye and Donald L. Bliwise and Kathy P. Parker and Lynn Marie Trotti and Prabhjyot Saini and Jacqueline A. Fairley and Amanda A. H. Freeman and Paul S. Garc{\'i}a and Michael J. Owens and James C. Ritchie and Andrew Jenkins},
  journal={Science Translational Medicine},
  year={2012},
  volume={4},
  pages={161ra151 - 161ra151}
}

• D. Rye, D. Bliwise, +8 authors A. Jenkins
• Published 21 November 2012
• Biology, Psychology
• Science Translational Medicine

A component of cerebrospinal fluid in excessively sleepy people activates an inhibitory signaling pathway and mimics the actions of sedative-hypnotics. Awake and Refreshed A spindle prick on the finger, and Princess Aurora couldn’t keep her eyes open; one hundred years later, Sleeping Beauty was awakened with a kiss. But persistent daytime sleepiness—hypersomnolence—is no fairy tale, and neither the cause nor a cure is apparent. Now, Rye et al. begin to illuminate, in patients with primary hypersomnias, the neurobiology that underlies sleepiness of unknown etiology. A disabling condition, primary hypersomnia is characterized by lethargy, trance-like states, and “sleep drunkenness” even after prolonged, deep, nonrestorative sleep. The authors showed that cerebrospinal fluid (CSF) from these hypersomnolent subjects contains a small (500 to 3000 daltons) trypsin-sensitive substance that stimulates the in vitro function of selected γ-aminobutyric acid (GABA) receptors only in the presence of GABA—an inhibitory neurotransmitter that stimulates GABA receptors, quells consciousness, and induces sleep. GABA receptors are known to bind a class of psychoactive sedating drugs called benzodiazepines (BZDs). Hypersomnolent CSF samples mimicked the effects of BZD on GABA receptors but did not compete with BZD binding in human brain tissue, suggesting that the newly identified substance functions by a distinct mechanism. Furthermore, the BZD receptor antagonist flumazenil reversed hypersomnolent-CSF activation of GABA signaling, even though the drug is known to be a competitive antagonist of BZD and blocks BZD action by binding to the classical BZD-binding domain of GABA receptors. Most importantly, flumazenil restored vigilance in some hypersomnolent subjects. Together, these mechanistic studies pinpoint a potential new neuropharmacological pathway for a 25-year-old drug. The current study suggests that one of the “spindle pricks” that puts hypersomnolent subjects to sleep is a substance in CSF that augments inhibitory GABA signaling. A deeper understanding of the neurobiology of primary hypersomnia should help scientists discover new “kisses” that restore wakefulness—in fewer than 100 years. The biology underlying excessive daytime sleepiness (hypersomnolence) is incompletely understood. After excluding known causes of sleepiness in 32 hypersomnolent patients, we showed that, in the presence of 10 μM γ-aminobutyric acid (GABA), cerebrospinal fluid (CSF) from these subjects stimulated GABAA receptor function in vitro by 84.0 ± 40.7% (SD) relative to the 35.8 ± 7.5% (SD) stimulation obtained with CSF from control subjects (Student’s t test, t = 6.47, P < 0.0001); CSF alone had no effect on GABAA signaling. The bioactive CSF component had a mass of 500 to 3000 daltons and was neutralized by trypsin. Enhancement was greater for α2 subunit– versus α1 subunit–containing GABAA receptors and negligible for α4 subunit–containing ones. CSF samples from hypersomnolent patients also modestly enhanced benzodiazepine (BZD)–insensitive GABAA receptors and did not competitively displace BZDs from human brain tissue. Flumazenil—a drug that is generally believed to antagonize the sedative-hypnotic actions of BZDs only at the classical BZD-binding domain in GABAA receptors and to lack intrinsic activity—nevertheless reversed enhancement of GABAA signaling by hypersomnolent CSF in vitro. Furthermore, flumazenil normalized vigilance in seven hypersomnolent patients. We conclude that a naturally occurring substance in CSF augments inhibitory GABA signaling, thus revealing a new pathophysiology associated with excessive daytime sleepiness.