Cortical network dysfunction caused by a subtle defect of myelination

• Published in: Glia Vol. 64; no. 11; pp. 2025 - 2040
• Main Authors: Poggi, Giulia, Boretius, Susann, Möbius, Wiebke, Moschny, Nicole, Baudewig, Jürgen, Ruhwedel, Torben, Hassouna, Imam, Wieser, Georg L., Werner, Hauke B., Goebbels, Sandra, Nave, Klaus-Armin, Ehrenreich, Hannelore
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2016; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase - genetics; 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase - metabolism; Age Factors; Animals; catatonia; Cnp mutant; Disease Models, Animal; electron microscopy; Exploratory Behavior - physiology; Female; Leukoencephalopathies - diagnostic imaging; Leukoencephalopathies - genetics; Leukoencephalopathies - pathology; Leukoencephalopathies - physiopathology; Maze Learning - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia - metabolism; Microglia - pathology; Microglia - ultrastructure; MRI; myelin basic protein (Mbp) mutant; Myelin Basic Protein - genetics; Myelin Basic Protein - metabolism; Myelin Sheath - genetics; Myelin Sheath - metabolism; Myelin Sheath - ultrastructure; Neural Pathways - metabolism; Neural Pathways - pathology; Neural Pathways - physiopathology; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; NMR; Nuclear magnetic resonance; Pregnancy; prepulse inhibition; Prepulse Inhibition - genetics; Reflex, Startle - genetics; White Matter - pathology; White Matter - ultrastructure; catatonia; electron microscopy; prepulse inhibition; Cnp mutant; myelin basic protein (Mbp) mutant; MRI
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.23039

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 Main Points We provide first experimental proof that a minor CNS myelination defect (Mbp+/‐) can cause cortical network dysfunction. This dysfunction is associated with subtle inflammation and late‐onset catatonia, phenotypes highly relevant for mental disease.