Selective loss of GABA
            <sub>B</sub>
            receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

Matsuki, Taizo; Nomiyama, Mika; Takahira, Hitomi; Hirashima, Noriko; Kunita, Satoshi; Takahashi, Satoru; Yagami, Ken Ichi; Kilduff, Thomas S.; Bettler, Bernhard; Yanagisawa, Masashi; Sakurai, Takeshi

doi:10.1073/pnas.0811126106

Cited by 114 publications

(95 citation statements)

References 37 publications

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“…To this end, the Rosa26 tm(HA)1Lib mice (20) were crossed with the Orex-Cre animals, expressing Cre under the control of the human orexin promoter (21).…”

Section: Resultsmentioning

confidence: 99%

“…The (BALB/cJ × C57BL/6J) F1-Orex-HA mice were generated by crossing the BALB/cJ-Rosa26 tm(HA)1Lib mice (20) with the C57BL/6J Orex-Cre mice, a gift from T. Sakurai, Kanazawa University, Kanazawa, Japan (21). In the resulting double-transgenic Orex-HA mice, the expression of HA of an H1N1 influenza virus, which is otherwise prevented by an upstream floxed Stop cassette, was induced because of the expression of the Cre recombinase specifically in orexin + neurons.…”

Section: Methodsmentioning

confidence: 99%

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CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin + neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin + neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin + neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin + neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin + neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.arcolepsy with cataplexy, referred to as type 1 narcolepsy (T1N), is a rare and chronic neurological disease characterized by excessive daytime sleepiness, sudden loss of muscle tone triggered by emotions (cataplexy), sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep (1). T1N is caused by a defective neurotransmission by the orexin/hypocretin neuropeptide and is associated with a selective and almost complete loss (85-100%) of orexinergic neurons in the hypothalamus (2, 3). The mechanisms leading to this neuronal loss are not yet elucidated, although current evidence points to an autoimmune process. Indeed, T1N is tightly associated with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, carried by 98.4% of patients vs. 17.7% of the general European population (4). An independent association with HLA class I alleles was recently revealed in two independent studies (5, 6). Additionally, an association with polymorphisms in the T-cell receptor (TCR) α chain locus was found and replicated (7,8). Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11)....

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“…To this end, the Rosa26 tm(HA)1Lib mice (20) were crossed with the Orex-Cre animals, expressing Cre under the control of the human orexin promoter (21).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

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“…Using transgenic mice in which Cre-recombinase is expressed exclusively in orexin neurons (orexin-cre transgenic mice) [12], these receptors were expressed solely on orexin neurons by transfection with adeno-associated virus (AAV) vectors utilizing the flipexcision method, which restores the open reading frame in a Cre-dependent manner [13,14] (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice

Suzuki

Mieda

et al. 2011

Neuroscience Research

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Hypothalamic neurons expressing neuropeptide orexins are critically involved in the control of sleep and wakefulness. Although the activity of orexin neurons is thought to be influenced by various neuronal input as well as humoral factors, the direct consequences of changes in the activity of these neurons in an intact animal are largely unknown. We therefore examined the effects of orexin neuron-specific pharmacogenetic modulation in vivo by a new method called the Designer Receptors Exclusively Activated by Designer Drugs approach (DREADD). Using this system, we successfully activated and suppressed orexin neurons as measured by Fos staining. EEG and EMG recordings suggested that excitation of orexin neurons significantly increased the amount of time spent in wakefulness and decreased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep times. Inhibition of orexin neurons decreased wakefulness time and increased NREM sleep time. These findings clearly show that changes in the activity of orexin neurons can alter the behavioral state of animals and also validate this novel approach for manipulating neuronal activity in awake, freely-moving animals.

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“…Selective deletion of GABA B receptors in orexin neurons results in highly unstable sleep/wake architecture in mice [43] , indicating that …”

Section: Sleep/wakefulness and Narcolepsymentioning

confidence: 99%

Central functions of the orexinergic system

Zhang

Zhuang

et al. 2013

Neurosci. Bull.

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The neuropeptide orexin is synthesized by neurons exclusively located in the hypothalamus. However, these neurons send axons over virtually the entire brain and spinal cord and therefore constitute a unique central orexinergic system. it is well known that central orexin plays a crucial role in the regulation of various basic non-somatic and somatic physiological functions, including feeding, energy homeostasis, the sleep/wake cycle, reward, addiction, and neuroendocrine, as well as motor control. Moreover, the absence of orexin results in narcolepsy-cataplexy, a simultaneous somatic and non-somatic dysfunction. in this review, we summarize these central functions of the orexinergic system and associated diseases, and suggest that this system may hold a key position in somatic-non-somatic integration.

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Selective loss of GABA _B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

Abstract: The authors note that due to a printer's error, on page 4460, Fig. 2 appears incorrectly in part. The middle and bottom panels were transposed. The corrected figure and its legend appear below. MGAS5005∆ccpA comp∆ccpA

Cited by 114 publications

References 37 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice

Central functions of the orexinergic system

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Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

Abstract: The authors note that due to a printer's error, on page 4460, Fig. 2 appears incorrectly in part. The middle and bottom panels were transposed. The corrected figure and its legend appear below. MGAS5005∆ccpA comp∆ccpA

Cited by 114 publications

References 37 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice

Central functions of the orexinergic system

Contact Info

Product

Resources

About

Selective loss of GABA _B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture