Wendy B. Macklin, Elizabeth Gould, Diego Restrepo
Department of Cell and Developmental Biology, University of Colorado School of Medicine.
Myelin is required for proper nerve conduction and has an important role in normal neuronal function. Polymorphisms in myelin genes are associated with neurologic and psychiatric diseases. However, little is known about the neuronal and behavioral consequences of myelin disruption and the role of myelin genes in pathology. To address the contribution of myelin function to behavioral and cognitive deficits, we investigated behavior in the proteolipid protein (PLP)-null mouse. These mice generate myelin but they exhibit progressive myelin dysfunction and subsequent axonal degeneration. We tested 3 and 8 month-old PLP knockout PLP(-/Y) male mice in several behavioral tests. No motor deficits were observed in 3 and 8 month old PLP(-/Y) mice on the Rotarod, a classical test of motor function. In an open field test, 8 month PLP(-/Y) mice spent less time in the center of the open field, while exploration of the walls was increased. PLP(-/Y) mice had decreased motivation to bury marbles in the marble burying task, in which the number of marbles buried in 10 minutes is quantified. This is an instinctive behavior, but 3 month PLP(-/Y) mice buried fewer marbles and by 8 months they buried almost none. Their performance on the Y maze, a test of spatial memory and hippocampal function, was normal at both ages.  However, their behavior in the Puzzle Box, a test of problem-solving and executive function, suggested deficits in problem solving. The Puzzle Box involves moving from a lighted box into a darkened goal box. The entry to the goal box becomes increasingly difficult, initially by covering it, then putting sawdust into it and finally covering the sawdust-filled entry. The 3 and 8 month PLP(-/Y) mice displayed cognitive deficits evidenced by longer latency to reach the goal box when presented with the new challenges. Intriguingly, 3 and 8 month PLP(-/Y) mice exhibit a significant increase in immobility and a lack of coordinated swimming behavior when placed in water.  We are currently investigating why there is a swimming deficit in PLP(-/Y) mice.  These behavioral results indicate that myelin dysfunction prior to significant axonal degeneration results in targeted behavioral deficits and cognitive dysfunction. Ongoing investigation aims at refining the characterization of these deficits and linking them to structural alteration of myelin in specific areas of the brain. Supported by NS25304.