title: Preserved functional autonomic phenotype in adult mice overexpressing moderate levels of human alpha-synuclein in oligodendrocytes.
abstract: Mice overexpressing human alpha-synuclein in oligodendrocytes (MBP1-α-syn) recapitulate some key functional and neuropathological features of multiple system atrophy (MSA). Whether or not these mice develop severe autonomic failure, which is a key feature of human MSA, remains unknown. We explored cardiovascular autonomic regulation using long-term blood pressure (BP) radiotelemetry and pharmacological testing. We instrumented 12 MBP1-α-syn mice and 11 wild-type mice aged 9 months for radiotelemetry. Animals were tested with atropine, metoprolol, clonidine, and trimethaphan at 9 and 12 months age. We applied spectral and cross-spectral analysis to assess heart rate (HR) and BP variability. At 9 months of age daytime BP (transgenic: 101 ± 2 vs. wild type: 99 ± 2 mmHg) and HR (497 ± 11 vs. 505 ± 16 beats/min) were similar. Circadian BP and HR rhythms were maintained. Nighttime BP (109 ± 2 vs. 108 ± 2 mmHg) and HR (575 ± 15 vs. 569 ± 14 beats/min), mean arterial BP responses to trimethaphan (-21 ± 8 vs. -10 ± 5 mmHg, P = 0.240) and to clonidine (-8 ± 3 vs. -5 ± 2 mmHg, P = 0.314) were similar. HR responses to atropine (+159 ± 24 vs. +146 ± 22 beats/min), and to clonidine (-188 ± 21 vs. -163 ± 33 beats/min) did not differ between strains. Baroreflex sensitivity (4 ± 1 vs. 4 ± 1 msec/mmHg) and HR variability (total power, 84 ± 17 vs. 65 ± 21 msec²) were similar under resting conditions and during pharmacological testing. Repeated measurements at 12 months of age provided similar results. In mice, moderate overexpression of human alpha-synuclein in oligodendrocytes is not sufficient to induce overt autonomic failure. Additional mechanisms may be required to express the autonomic failure phenotype including higher levels of expression or more advanced age.
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Tank
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Andrey C
authors.initials: AC
authors.lastname: da Costa-Goncalves
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kamer
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Autonomic Dysfunction Service, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: André
authors.initials: A
authors.lastname: Diedrich
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
keywords: Autonomic failure; blood pressure; human alpha‐synuclein; multiple system atrophy; transgenic mice