MYELIN MOSAICISM AND BRAIN PLASTICITY IN HETEROZYGOUS FEMALES OF A CANINE X-LINKED TRAIT

The shaking (sh) pup, an animal model of Pelizaeus-Merzbacher disease, is characterized by severe central nervous system dysmyelination in a ffected males, and myelin mosaicism in some female heterozygotes as a result of X-linked inactivation. Heterozygous females develop a tremor of varying severity that usually disappears at 4 to 6 weeks, whereas male hemizygotes have severe, generalized tremor that persists through out life. We have used these two myelin-deficient models to study the potential for recovery with time as reflected by brainstem auditory ev oked responses (BAERs). At set time points, the state of myelination i n the trapezoid body was studied microscopically. Sequential BAERs dem onstrated consistently prolonged interpeak latencies during the period of gross tremor in heterozygotes, with the trend continuing to a less er extent after tremor cessation. The random nature of X-linked inacti vation resulted in variable myelin mosaicism that was reflected in var iations in BAER changes within animals in the same litter. In most het erozygotes, the tremor resolved with time, the BAERs returned to near normal, and myelin mosaicism was test. In contrast, in the affected ma les, the severity of tremor and lack of recovery was demonstrated by c onsistent abnormalities in BAER waves at all times studied, and severe and persistent myelin deficiency in the trapezoid body. These finding s show that despite the normal tightly programmed temporal development of myelin in the brain in the heterozygous mosaic state, sufficient p lasticity persists during the neonatal period for late-stage myelinati on to occur.