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Experimental Genetics Group
J Neurosci. 2010 Feb 3;30(5):1810-21. Dutschmann M1,2*, Menuet C3*, Stettner GM4, Gestreau C3, Borghgraef P5, Devijver H5, Gielis L5, Hilaire G3, Van Leuven F5. 1Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. 2Bernstein Center for Computational Neurosciences, D-37073 Göttingen, Germany. 3MP3-Respiration, Centre de Recherche de Neurobiologie-Neurophysiologie de Marseille, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6231, Faculté Saint Jérôme, 13397 Marseille, France. 4Department of Pediatrics and Pediatric Neurology, University Medicine Göttingen, Georg August University, D-37075 Göttingen, Germany. 5Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. *M.D., C.M., and G.M.S. contributed equally to this work. Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer’s disease, the most frequent secondary tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7– 8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo doublechamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Ko¨lliker–Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive tauopathy in identified neural circuits. Because patients with tauopathy suffer from upper airway dysfunction, the Tau- P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.  FULL TEXT |
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