Seizures, ataxia, and neuronal loss in cystatin B heterozygous mice

Unverricht-Lundborg disease (EPM1) has been considered to be an autosomal-recessive disease related with loss of function mutations in the gene encoding cystatin B. Although heterozygous carriers are generally asymptomatic, earlier studies in Finnish EPM1 families have reported minor symptoms together with slight changes in the EEG recordings also in near relatives of patients. Here we tested the hypothesis that EPM1 phenotype is expressed also in heterozygous subjects using 17-month-old cystatin B deficient mice as a model of disease. Western blot analysis demonstrated a 50% decrease in cystatin B expression in the cerebellum of these animals. Heterozygous mice showed significantly impaired rotarod performance and were weaker in the grid test. Also the total seizure-rating score of heterozygous animals was higher than in wild-type mice. The stereological analysis revealed a significant decrease in the number of neurons in cerebral cortex and the granule cell layer of cerebellum. These results suggest that partial decrease in cystatin B expression in heterozygous mice could lead to the development of mild EPM1 phenotype.