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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

Cataplexy and sleep-wake derangements.(A) Frequency of occurrence of cataplexy-like episodes (CLE) during the dark period. In this and the remaining panels, data are means ± SEM in HDC-KO (n = 11), DM (n = 7), and WT (n = 11). (B) Representative raw tracings (EEG, electroencephalogram; EMG, electromyogram) showing a CLE (arrow) in a DM mouse. Details of the transition between wakefulness (W) and this CLE are shown in (C), evidencing an almost complete drop in neck muscle tone with preservation of the theta frequency rhythm of the preceding episode of W. (D) Frequency of occurrence of W episodes as a function of their duration. The distribution of W durations was significantly different between HDC-KO, DM, and WT (P < 0.001, Kolmogorov-Smirnov test). The bar graphs in (E) show the frequency of occurrence of W episodes in four arbitrary bins of W episode duration. (F) Percentage of recording time spent in rapid-eye-movement sleep (R). The horizontal bar refers to the whole dark period. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests).
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pone.0140520.g002: Cataplexy and sleep-wake derangements.(A) Frequency of occurrence of cataplexy-like episodes (CLE) during the dark period. In this and the remaining panels, data are means ± SEM in HDC-KO (n = 11), DM (n = 7), and WT (n = 11). (B) Representative raw tracings (EEG, electroencephalogram; EMG, electromyogram) showing a CLE (arrow) in a DM mouse. Details of the transition between wakefulness (W) and this CLE are shown in (C), evidencing an almost complete drop in neck muscle tone with preservation of the theta frequency rhythm of the preceding episode of W. (D) Frequency of occurrence of W episodes as a function of their duration. The distribution of W durations was significantly different between HDC-KO, DM, and WT (P < 0.001, Kolmogorov-Smirnov test). The bar graphs in (E) show the frequency of occurrence of W episodes in four arbitrary bins of W episode duration. (F) Percentage of recording time spent in rapid-eye-movement sleep (R). The horizontal bar refers to the whole dark period. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests).

Mentions: CLE during the dark period were detected in each DM mouse, but were absent in HDC-KO and WT (Fig 2A–2C). DM also showed fragmentation of wakefulness by sleep attacks (Fig 2D and 2E) and spent more time in R during the dark period (Fig 2F) compared to either WT or HDC-KO. No significant differences occurred between HDC-KO and WT. The percentage of time spent in wakefulness and non-rapid-eye-movement sleep (N) at baseline, and the responsiveness to a 6-hour sleep deprivation intervention in terms of sleep time and EEG slow-wave activity did not differ significantly among HDC-KO, DM, and WT (S1 and S2 Figs).


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)

Cataplexy and sleep-wake derangements.(A) Frequency of occurrence of cataplexy-like episodes (CLE) during the dark period. In this and the remaining panels, data are means ± SEM in HDC-KO (n = 11), DM (n = 7), and WT (n = 11). (B) Representative raw tracings (EEG, electroencephalogram; EMG, electromyogram) showing a CLE (arrow) in a DM mouse. Details of the transition between wakefulness (W) and this CLE are shown in (C), evidencing an almost complete drop in neck muscle tone with preservation of the theta frequency rhythm of the preceding episode of W. (D) Frequency of occurrence of W episodes as a function of their duration. The distribution of W durations was significantly different between HDC-KO, DM, and WT (P < 0.001, Kolmogorov-Smirnov test). The bar graphs in (E) show the frequency of occurrence of W episodes in four arbitrary bins of W episode duration. (F) Percentage of recording time spent in rapid-eye-movement sleep (R). The horizontal bar refers to the whole dark period. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140520.g002: Cataplexy and sleep-wake derangements.(A) Frequency of occurrence of cataplexy-like episodes (CLE) during the dark period. In this and the remaining panels, data are means ± SEM in HDC-KO (n = 11), DM (n = 7), and WT (n = 11). (B) Representative raw tracings (EEG, electroencephalogram; EMG, electromyogram) showing a CLE (arrow) in a DM mouse. Details of the transition between wakefulness (W) and this CLE are shown in (C), evidencing an almost complete drop in neck muscle tone with preservation of the theta frequency rhythm of the preceding episode of W. (D) Frequency of occurrence of W episodes as a function of their duration. The distribution of W durations was significantly different between HDC-KO, DM, and WT (P < 0.001, Kolmogorov-Smirnov test). The bar graphs in (E) show the frequency of occurrence of W episodes in four arbitrary bins of W episode duration. (F) Percentage of recording time spent in rapid-eye-movement sleep (R). The horizontal bar refers to the whole dark period. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests).
Mentions: CLE during the dark period were detected in each DM mouse, but were absent in HDC-KO and WT (Fig 2A–2C). DM also showed fragmentation of wakefulness by sleep attacks (Fig 2D and 2E) and spent more time in R during the dark period (Fig 2F) compared to either WT or HDC-KO. No significant differences occurred between HDC-KO and WT. The percentage of time spent in wakefulness and non-rapid-eye-movement sleep (N) at baseline, and the responsiveness to a 6-hour sleep deprivation intervention in terms of sleep time and EEG slow-wave activity did not differ significantly among HDC-KO, DM, and WT (S1 and S2 Figs).

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