title: Cortical network dysfunction caused by a subtle defect of myelination.
abstract: Subtle white matter abnormalities have emerged as a hallmark of brain alterations in magnetic resonance imaging or upon autopsy of mentally ill subjects. However, it is unknown whether such reduction of white matter and myelin contributes to any disease-relevant phenotype or simply constitutes an epiphenomenon, possibly even treatment-related. Here, we have re-analyzed Mbp heterozygous mice, the unaffected parental strain of shiverer, a classical neurological mutant. Between 2 and 20 months of age, Mbp(+/-) versus Mbp(+/+) littermates were deeply phenotyped by combining extensive behavioral/cognitive testing with MRI, 1H-MR spectroscopy, electron microscopy, and molecular techniques. Surprisingly, Mbp-dependent myelination was significantly reduced in the prefrontal cortex. We also noticed a mild but progressive hypomyelination of the prefrontal corpus callosum and low-grade inflammation. While most behavioral functions were preserved, Mbp(+/-) mice exhibited defects of sensorimotor gating, as evidenced by reduced prepulse-inhibition, and a late-onset catatonia phenotype. Thus, subtle but primary abnormalities of CNS myelin can be the cause of a persistent cortical network dysfunction including catatonia, features typical of neuropsychiatric conditions. GLIA 2016;64:2025-2040.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Giulia
authors.initials: G
authors.lastname: Poggi
authors.affiliation: Department of Radiology and Neuroradiology, Christian-Albrechts-University, Kiel.|Department of Functional Imaging, German Primate Center, Leibniz Institute of Primate Research, Göttingen.
authors.forename: Susann
authors.initials: S
authors.lastname: Boretius
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Möbius
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Nicole
authors.initials: N
authors.lastname: Moschny
authors.affiliation: Department of Radiology and Neuroradiology, Christian-Albrechts-University, Kiel.|Department of Functional Imaging, German Primate Center, Leibniz Institute of Primate Research, Göttingen.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Baudewig
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Torben
authors.initials: T
authors.lastname: Ruhwedel
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Imam
authors.initials: I
authors.lastname: Hassouna
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Georg L
authors.initials: GL
authors.lastname: Wieser
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Hauke B
authors.initials: HB
authors.lastname: Werner
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen.
authors.forename: Sandra
authors.initials: S
authors.lastname: Goebbels
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen. nave@em.mpg.de.|DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. nave@em.mpg.de.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen. ehrenreich@em.mpg.de.|DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. ehrenreich@em.mpg.de.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D056784:Leukoencephalopathies / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D065808:Prepulse Inhibition / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics; D066127:White Matter / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D004676:Myelin Basic Protein; D052247:Nitric Oxide Synthase Type II; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571338:Cnp protein, mouse
keywords: Cnp mutant; MRI; catatonia; electron microscopy; myelin basic protein (Mbp) mutant; prepulse inhibition