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Cortical network dysfunction caused by a subtle defect of myelination
Giulia Poggi1, Susann Boretius2,3, Wiebke Möbius4
1Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen.
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.
Insights
Subtle white matter abnormalities in Mbp(+/-) mice led to reduced prefrontal cortex myelination. This primary myelin defect caused sensorimotor gating deficits and catatonia, suggesting a cause for neuropsychiatric conditions.
Area of Science:
- Neuroscience
- Neurobiology
- Genetics
Background:
- White matter abnormalities are observed in mentally ill individuals.
- The role of reduced white matter and myelin in disease phenotypes is unclear.
- Mbp heterozygous mice, a model related to neurological mutants, were studied.
Purpose of the Study:
- To investigate if subtle white matter abnormalities in Mbp(+/-) mice contribute to disease-relevant phenotypes.
- To explore the consequences of reduced myelin in the central nervous system (CNS).
Main Methods:
- Comprehensive phenotyping of Mbp(+/-) and Mbp(+/+) mice from 2 to 20 months of age.
- Utilized behavioral/cognitive testing, MRI, 1H-MR spectroscopy, electron microscopy, and molecular techniques.
- Analyzed myelination, inflammation, and behavioral functions.
Main Results:
- Significantly reduced Mbp-dependent myelination in the prefrontal cortex of Mbp(+/-) mice.
- Mild, progressive hypomyelination of the prefrontal corpus callosum and low-grade inflammation observed.
- Mbp(+/-) mice showed preserved general behavior but deficits in sensorimotor gating (reduced prepulse inhibition) and late-onset catatonia.
Conclusions:
- Subtle, primary abnormalities in CNS myelin can cause persistent cortical network dysfunction.
- Catatonia and other features observed in Mbp(+/-) mice are typical of neuropsychiatric conditions.
- This study links primary myelin defects to neurological and psychiatric phenotypes.
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