PT - JOURNAL ARTICLE AU - Rye, David B. AU - Bliwise, Donald L. AU - Parker, Kathy AU - Trotti, Lynn Marie AU - Saini, Prabhjyot AU - Fairley, Jacqueline AU - Freeman, Amanda AU - Garcia, Paul S. AU - Owens, Michael J. AU - Ritchie, James C. AU - Jenkins, Andrew TI - Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABA<sub>A</sub> Receptors AID - 10.1126/scitranslmed.3004685 DP - 2012 Nov 21 TA - Science Translational Medicine PG - 161ra151--161ra151 VI - 4 IP - 161 4099 - http://stm.sciencemag.org/content/4/161/161ra151.short 4100 - http://stm.sciencemag.org/content/4/161/161ra151.full AB - 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 &lt; 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.