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Histamine Transmission Modulates the Phenotype of Murine Narcolepsy Caused by Orexin Neuron Deficiency.

Bastianini S, Silvani A, Berteotti C, Lo Martire V, Cohen G, Ohtsu H, Lin JS, Zoccoli G - PLoS ONE (2015)

Bottom Line: Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine.Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM.Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

View Article: PubMed Central - PubMed

Affiliation: PRISM Laboratory, Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

ABSTRACT
Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness, cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine. Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

No MeSH data available.


Related in: MedlinePlus

Narcolepsy characteristics described in different strains of male genetically-engineered orexin-deficient mice.HCRT-ataxin3-Tg: mice hemizygous for a transgene (hypocretin-ataxin3) coding for a neurotoxin, which causes selective ablation of orexin neurons; HCRT-KO: hypocretin gene knock-out mice with congenital deficiency of orexins.
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pone.0140520.g001: Narcolepsy characteristics described in different strains of male genetically-engineered orexin-deficient mice.HCRT-ataxin3-Tg: mice hemizygous for a transgene (hypocretin-ataxin3) coding for a neurotoxin, which causes selective ablation of orexin neurons; HCRT-KO: hypocretin gene knock-out mice with congenital deficiency of orexins.

Mentions: A remarkable feature of narcolepsy type 1 is its wide comorbidity spectrum, which includes metabolic [3], cardiovascular [4], and respiratory [5] anomalies. These comorbidities also occur in orexin-neuron deficient mice (Fig 1), making a strong case for a causal role of orexin neuron loss. However, it is still unclear whether these different narcolepsy traits result from orexin neuron loss directly, because of the loss of direct orexinergic projections to neural structures involved in sleep, metabolic, and cardiorespiratory control, or rather indirectly, because of secondary and possibly compensatory imbalances of other transmitter systems. This complexity may contribute to changes of the narcoleptic phenotype among and within subjects, including peculiarities of childhood narcolepsy [6].


Histamine Transmission Modulates the Phenotype of Murine Narcolepsy Caused by Orexin Neuron Deficiency.

Bastianini S, Silvani A, Berteotti C, Lo Martire V, Cohen G, Ohtsu H, Lin JS, Zoccoli G - PLoS ONE (2015)

Narcolepsy characteristics described in different strains of male genetically-engineered orexin-deficient mice.HCRT-ataxin3-Tg: mice hemizygous for a transgene (hypocretin-ataxin3) coding for a neurotoxin, which causes selective ablation of orexin neurons; HCRT-KO: hypocretin gene knock-out mice with congenital deficiency of orexins.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608736&req=5

pone.0140520.g001: Narcolepsy characteristics described in different strains of male genetically-engineered orexin-deficient mice.HCRT-ataxin3-Tg: mice hemizygous for a transgene (hypocretin-ataxin3) coding for a neurotoxin, which causes selective ablation of orexin neurons; HCRT-KO: hypocretin gene knock-out mice with congenital deficiency of orexins.
Mentions: A remarkable feature of narcolepsy type 1 is its wide comorbidity spectrum, which includes metabolic [3], cardiovascular [4], and respiratory [5] anomalies. These comorbidities also occur in orexin-neuron deficient mice (Fig 1), making a strong case for a causal role of orexin neuron loss. However, it is still unclear whether these different narcolepsy traits result from orexin neuron loss directly, because of the loss of direct orexinergic projections to neural structures involved in sleep, metabolic, and cardiorespiratory control, or rather indirectly, because of secondary and possibly compensatory imbalances of other transmitter systems. This complexity may contribute to changes of the narcoleptic phenotype among and within subjects, including peculiarities of childhood narcolepsy [6].

Bottom Line: Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine.Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM.Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

View Article: PubMed Central - PubMed

Affiliation: PRISM Laboratory, Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

ABSTRACT
Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness, cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine. Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

No MeSH data available.


Related in: MedlinePlus