Progressive gait and motor deficits in a rat model of Alexander disease.

Abstract

Alexander disease is a leukodystrophy caused by gain-of-function mutations in the gene for Glial Fibrillary Acidic Protein (GFAP) which result in accumulation and aggregation of GFAP protein, astrocyte dysfunction, and ultimately developmental delay, failure to thrive, and intellectual and motor impairment. A Gfaprat model, designed to mimic the common R239H human variant, meets normal milestones during early postnatal development, but declines dramatically as the rats mature. At severe stages of disease, Gfaprats exhibit cognitive and motor deficits and increased mortality. Here we provide a more detailed analysis of the Gfaprat with respect to onset of motor impairments and increasing loss of function. We show that Gfaprats develop abnormal open field activity as they mature but stabilize with age, and that motor deficits are apparent as early as 4 weeks of age, as demonstrated by poor rotarod performance. We use automated gait analysis to further characterize subtle differences at this early age and demonstrate the progression and persistence of impairment at late stages of disease. In addition, we find evidence for changes in cerebellar size, suggesting a potential neuroanatomical correlate to the observed deficits. The rat model provides a novel system in which to investigate aspects of impaired motor function and central nervous system pathology that are directly relevant to the human disease.