Objective: The pathophysiology of idiopathic hypersomnia (IH) remains unclear. Recently, cerebrospinal fluid (CSF)-induced enhancement of c-aminobutyric acid (GABA)-A receptor activity was found in patients with IH compared to controls. Methods: Fifteen unrelated patients (2 males and 13 females) affected with typical IH, 12 patients (9 males and 3 females) with narcolepsy type 1, and 15 controls (9 males and 6 females) with unspecified hypersomnolence (n 5 7) and miscellaneous neurological conditions (n 5 8) were included. A lumbar puncture was performed in all participants to measure CSF hypocretin-1 and GABA-A response. We used a voltage-clamp assay on Xenopus oocytes injected with the RNAs that encode the a 1 b 2 c 2 or the a 2 b 2 c 2 subunits of the human GABA-A receptor. A sequence of 6 different applications (GABA, GABA/CSF, and CSF alone) with 2 to 4 oocytes per CSF sample was performed in a whole-cell voltage-clamp assay. Results: Representative current traces from oocytes expressing human a 1 b 2 c 2 or a 2 b 2 c 2 GABA-A receptors were recorded in response to 6 successive puffs of GABA diluted in the survival medium (SM), showing stable and reliable response. GABA puffs diluted in SM/CSF solution or SM/CSF solution alone showed no significant differences in the CSF of IH, narcolepsy, or control groups. No associations were found between GABA responses, demographic features , disease duration, or disease severity in the whole population or within groups. Interpretation: Using the Xenopus oocyte assay, we found an absence of GABA-A receptor potentiation with CSF from patients with central hypersomnolence disorders, with no significant differences between hypocretin-deficient and non–hypocretin-deficient patients compared to controls. ANN NEUROL 2016;80:259–268 I diopathic hypersomnia (IH) is an orphan sleep disorder , clinically characterized by excessive daytime sleepi-ness (EDS) with long and unrefreshing naps, prolonged and undisturbed nocturnal sleep, and great difficulty waking up after sleep, called sleep inertia. 1 The main features of IH are normal nighttime sleep with high sleep efficiency and high percentage of deep (slow wave) non– rapid eye movement (NREM) sleep on polysomnography (PSG), with either decreased mean sleep latencies with <2 sleep onset REM periods (SOREMPs) on the multiple sleep latency test (MSLT) or prolonged time " asleep " on continuous PSG or actigraphy (total sleep time 11 hours on 24-hour monitoring) without sleep apnea or periodic limb movements. 2,3 IH is rarely the cause of central hypersomnolence disorder, but is instead an exclusion diagnosis, with a broad differential diagnosis including narcolepsy without cataplexy, atypical forms of depression, sleep apnea syndrome, and behaviorally induced insufficient sleep syndrome, although there are overlaps with these conditions. 4–6 The neurobiology of IH remains unclear. Whereas wakefulness is largely promoted by neurons from the pons, midbrain, and posterior hypothalamus that release acetylcholine, norepinephrine, dopamine, serotonin, View this article online at wileyonlinelibrary.com.