Aspects of the narcolepsy-cataplexy syndrome in O/E3-null mutant mice

• Published in: Neuroscience Vol. 183; pp. 134 - 143
• Main Authors: De La Herrán-Arita, A.K, Zomosa-Signoret, V.C, Millán-Aldaco, D.A, Palomero-Rivero, M, Guerra-Crespo, M, Drucker-Colín, R, Vidaltamayo, R
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 02.06.2011; Elsevier
• Subjects: Animals; Arousal - drug effects; Basic Helix-Loop-Helix Transcription Factors - deficiency; Biological and medical sciences; Brain - pathology; Catalepsy; Cell Count; Circadian Rhythm - physiology; CNS development; Disease Models, Animal; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Electroencephalography; Electromyography; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - genetics; Guinea Pigs; hypothalamus; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Signaling Peptides and Proteins - therapeutic use; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Narcolepsy - drug therapy; Narcolepsy - genetics; Narcolepsy - pathology; Narcolepsy - physiopathology; Nervous system (semeiology, syndromes); Neurology; Neurons - metabolism; Neuropeptides - metabolism; Neuropeptides - therapeutic use; Neurotransmitter Agents - therapeutic use; Orexins; sleep; Sleep. Vigilance; Trans-Activators - genetics; Trans-Activators - metabolism; transcription factors; Vertebrates: nervous system and sense organs; direct transition to REM; transcription factors; lateral hypothalamus; phosphate-buffered saline; rapid eye movement; electromyogram; sleep; pedunculopontine nuclei; DREM; CSF; ChAT; wildtype; non rapid eye movement; EMG; PBS; EEG; CNS development; electroencephalogram; melanin concentrating hormone; choline acetyltransferase; MCH; PPTg; cerebrospinal fluid; REM; LH; Wt; hypothalamus; nREM; Nervous system diseases; Rodentia; Central nervous system; Sleep disorder; Hypothalamus; Encephalon; Vertebrata; Mammalia; Sleep; Mouse; Animal; Development; Narcolepsy; Mutation; Neurological disorder; Transcription factor
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.03.029

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 of orexin 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 in orexin-producing cells in the LH, in addition to a severely impaired orexinergic innervation of the pons. These changes in the orexinergic circuit of O/E3-null 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 by controlling 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.