Pathological myelin outfoldings: cellular cause and behavioral consequences

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Myelination of axons facilitates rapid and precise impulse propagation in the nervous system, a prerequisite for normal motor, sensory and cognitive capabilities. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular causes and functional consequences of many pathological features have remained unknown, including the frequently observed myelin outfoldings. We have identified a previously unrecognized structure in the central nervous system, myelin septin filaments, which extend longitudinally along myelinated axons. Genetic disruption of these filaments in Sept8-mutant mice causes myelin outfoldings as a very specific neuropathology. The assembly of septin filaments during the maturation of myelin is thus required to scaffold the axon/myelin-unit. Based on our previous observations we propose to investigate the molecular factors mediating the assembly of myelin septins, the cellular forces driving the formation of myelin outfoldings and their consequences at the behavioral level. This project will involve mouse genetics, biochemistry, quantitative proteomics, electron microscopy and assessment of mouse behavior. Sept8-mutant mice provide a unique model to test the hypothesis that the reduced nerve conduction velocity due to myelin outfoldings is sufficient to cause behavioral impairment including abnormalities seen in psychiatric conditions; this novel concept will be tested in vivo.