Isolated catatonia-like executive dysfunction in mice with forebrain-specific loss of myelin integrity

Abstract

ABSTRACTA key feature of advanced brain aging includes structural defects of intracortical myelin that are associated with secondary neuroinflammation. A similar pathology is seen in specific myelin mutant mice that model ‘advanced brain aging’ and exhibit a range of behavioral abnormalities. However, the cognitive assessment of these mutants is problematic because myelin-dependent motor-sensory functions are required for quantitative behavioral readouts. To better understand the role of cortical myelin integrity for higher brain functions, we generated mice lackingPlp1, encoding the major integral myelin membrane protein, selectively in ventricular zone stem cells of the mouse forebrain. In contrast to conventionalPlp1null mutants, subtle myelin defects were restricted to the cortex, hippocampus and underlying callosal tracts. Moreover, forebrain-specificPlp1mutants exhibited no defect of basic motor-sensory performance at any age tested. Surprisingly, several behavioral alterations reported for conventionalPlp1null mice (Gould et al., 2018) were absent and even social interactions appeared normal. However, with novel behavioral paradigms, we determined catatonia-like symptoms and isolated executive dysfunction in both genders. This suggests that loss of myelin integrity has an impact on cortical connectivity and underlies specific defects of executive function. These observations are likewise relevant for human neuropsychiatric conditions and other myelin-related diseases.