Cortical network dysfunction caused by a subtle defect of myelination. Issue 11 (29th July 2016)

• Record Type: Journal Article
• 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
• Is Part Of: Glia. Volume 64:Issue 11(2016:Nov.)
• Page Start: 2025
• Page End: 2040
• Publication Date: 2016-07-29
• Subjects: myelin basic protein (Mbp) mutant -- Cnp mutant -- prepulse inhibition -- catatonia -- MRI -- electron microscopy; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23039
• Languages: English
• ISSNs: 0894-1491

Abstract

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 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.