Breathing variability and brainstem serotonergic loss in a genetic model of multiple system atrophy.

Olivier Flabeau, Wassilios G. Meissner, Annaig Ozier, Patrick Berger, François Tison, Pierre-Olivier Fernagut
Mov Disord.. 2014-01-17; 29(3): 388-395
DOI: 10.1002/mds.25804

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1. Mov Disord. 2014 Mar;29(3):388-95. doi: 10.1002/mds.25804. Epub 2014 Jan 17.

Breathing variability and brainstem serotonergic loss in a genetic model of
multiple system atrophy.

Flabeau O(1), Meissner WG, Ozier A, Berger P, Tison F, Fernagut PO.

Author information:
(1)Service de Neurologie, Centre Hospitalier Universitaire de Bordeaux, Pessac,

Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are
frequent in patients with multiple system atrophy (MSA). These observations have
been related to neurodegeneration in several pontomedullary respiratory nuclei
and may explain the occurrence of sudden death. In this study, we sought to
determine whether these functional and neuropathological characteristics could be
replicated in a transgenic model of MSA. Mice expressing human wild-type
α-synuclein under the control of the proteolipid promoter (PLP-αSYN) were
compared with age-matched controls. Using whole-body, unrestrained
plethysmography, the following breathing parameters were measured: inspiratory
and expiratory times, tidal volume, expiratory volume, peak inspiratory and
expiratory flows, and respiratory frequency. For each category, the mean,
coefficient of variation, and irregularity score were analyzed. Brains were then
processed for stereological cell counts of pontomedullary respiratory nuclei. A
significant increase in the coefficient of variation and irregularity score was
observed for inspiratory time, tidal volume, and expiratory volume in PLP-αSYN
mice (P < 0.05). Glial cytoplasmic inclusions were found in the medullary raphe
of PLP-αSYN mice, together with a loss of serotonergic immunoreactivity in the
raphe obscurus (P < 0.001) and pallidus (P < 0.01). There was a negative
correlation between α-synuclein burden and raphe pallidus cell counts (P < 0.05).
There was no significant neuronal loss in the pre-Botzinger complex. The PLP-αSYN
mouse model replicates the breathing variability and part of the neuronal
depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our
findings support the use of this model for future candidate drugs in the
breathing disorders observed in MSA.

© 2014 International Parkinson and Movement Disorder Society.

DOI: 10.1002/mds.25804
PMID: 24442757 [Indexed for MEDLINE]

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