Aspects Of The Narcolepsy-Cataplexy Syndrome In O/E3-Null Mutant Mice

Neuroscience 183 (2011) 134 -143

ASPECTS OF THE NARCOLEPSY-CATAPLEXY O/E3-NULL MUTANT MICE
A. K. DE LA HERRÁN-ARITA, a V. C. ZOMOSA-SIGNORET, b D. A. MILLÁN-ALDACO, a M. PALOMERO-RIVERO, a M. GUERRA-CRESPO, a R. DRUCKER-COLÍN a * AND R. VIDALTAMAYO a1 *
a Departamento de Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DistritoFederal, Mexico b Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Nuevo León, México

SYNDROME

IN

Abstract: Orexins (hypocretins) are peptide neurotransmitters produced by a small group of neurons located exclusively in the lateral hypothalamus (LH). Orexins modulate arousal, and as a result, have profound effects on feeding behavior and the sleep-wake cycle. Loss oforexin producing neurons leads to a narcoleptic phenotype, characterized by sudden transitions from vigilance to rapid eye movement (REM) sleep (direct transition to REM, DREM) observed in electroencephalogram (EEG) and electromyogram (EMG) recordings. In this study, we demonstrate that mice lacking the basic helix-loop-helix transcription factor O/E3 (also known as ebf2) have a decrease inorexin-producing cells in the LH, in addition to a severely impaired orexinergic innervation of the pons. These changes in the orexinergic circuit of O/E3null animals induce a narcoleptic phenotype, similar to the one arising in orexin-deficient and orexin-ataxin-3 mice. Taken together, our results suggest that O/E3 plays a central role during the establishment of a functional orexinergic circuit bycontrolling the expression of essential hypothalamic neurotransmitter and the correct development of the nerve fibers arising from the hypothalamus. This is the first report regarding the narcolepsy-cataplexy syndrome in O/E3-null mice, which adds the importance of transcription factors in the regulation of neural subpopulations that control the sleep-wake cycle. © 2011 IBRO. Published by ElsevierLtd. All rights reserved. Key words: CNS development, scription factors. hypothalamus, sleep, tran-

Orexins (orexin-A and B) are neuropeptides derived from a common precursor protein called prepro-orexin, whose expression is restricted to a small population of neurons residing in the LH (Broberger et al., 1998; Nambu et al.,
1 Present address: Center for Molecular Diagnostics andPersonalized Medicine, Universidad de Monterrey, Avenue Morones Prieto 4500, 66238 San Pedro Garza García, Nuevo León, Mexico. *Corresponding author. Tel: 52-55-5550-0064; fax: 52-55-55500064. E-mail address: drucker@servidor.unam.mx (R. Drucker-Colín). roman.vidal@udem.edu.mx (R. Vidaltamayo). Abbreviations: ChAT, choline acetyltransferase; CSF, cerebrospinal fluid; DREM, direct transition to REM; EEG,electroencephalogram; EMG, electromyogram; LH, lateral hypothalamus; MCH, melanin concentrating hormone; nREM, non rapid eye movement; PBS, phosphate-buffered saline; PPTg, pedunculopontine nuclei; REM, rapid eye movement; Wt, wildtype.

1999; Moriguchi et al., 2002). Albeit being a small cell group, orexinergic projections extensively innervate the CNS, reaching the cortex, pons, spinal cord andhypothalamus, where orexins modulate arousal (Peyron et al., 1998; Sakurai et al., 1998; Lin et al., 1999; Marcus et al., 2001; Tsujino and Sakurai, 2009) via interaction with two G-protein coupled receptors, OXR1 and OXR2 (Sakurai et al., 1998; de Lecea et al., 1998; Date et al., 1999). Perturbations of the orexinergic system, either at the neurotransmitter or the receptor level, lead todisruptions in the arousal system, resulting in a narcoleptic phenotype (Chemelli et al., 1999; Lin et al., 1999; Nishino et al., 2000; Peyron et al., 2000; Thannickal et al., 2000; Hara et al., 2001; Willie et al., 2003; Beuckmann et al., 2004). Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations (Nishino et al., 2000;...