Structural bases for central nervous system malfunction in the quaking mouse: dysmyelination in a potential model of...

The dysmyelinating mouse mutant quaking (qk) is thought to be a model of schizophrenia based on diminution of CNS myelin (Andreone et al., 2007) and downregulation of the Qk gene (Haroutunian et al., 2006) in the brains of schizophrenic patients. The purpose of this study was to identify specific structural defects in the qk mouse CNS that could compromise physiologic function and that in humans might account for some of the cognitive defects characteristic of schizophrenia. Ultrastructural analysis of qk mouse CNS myelinated fibers shows abnormalities in nodal, internodal, and paranodal regions, including marked variation in myelin thickness among neighboring fibers, spotty disruption of paranodal junctions, abnormal distribution of nodal and paranodal ion channel complexes, generalized thinning and incompactness of myelin, and on many axonal profiles complete absence of myelin. These structural defects are likely to cause abnormalities in conduction velocity, synchrony of activation, temporal ordering of signals, and other physiological parameters. We conclude that the structural abnormalities described are likely to be responsible for significant functional impairment both in the qk mouse CNS and in the human CNS with comparable myelin pathology.