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Experimental Genetics Group
J Neurosci. 2010 Feb 3; 30(5):1810-21. Mathias Dutschmann,1 , 2* Clement Menuet, 3* Georg M. Stettner,4* Christian Gestreau,3 Peter Borghgraef,5 Herman Devijver,5 Lies Gielis,5 Gerard Hilaire,3 and Fred Van Leuven5. 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, Unite´ Mixte de Recherche Centre National de la Recherche Scientifique 6231, Faculte´ Saint Je´roˆme, 13397 Marseille, France 4Department of Pediatrics and Pediatric Neurology, University Medicine Göttingen, Georg August University, D-37075 Goöttingen, Germany 5Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium 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 double-chamber 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 Kölliker-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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