DEVELOPMENT OF CEREBELLAR HYPOPLASIA IN JAUNDICED GUNN-RATS - A QUANTITATIVE LIGHT-MICROSCOPIC ANALYSIS

The homozygous (ij) Gunn rat provides a model for hyperbilirubinemia w hich includes prominent cerebellar hypoplasia. Development of the Gunn rat cerebellum was examined with and without the additional effects o f elevating brain bilirubin concentration to still higher levels via s ulfadimethoxine (sulfa) administration. Homozygous (jj) Gunn rats and heterozygous (Nj) littermate controls (n = 32 each) were given 100 mg/ kg sulfa or saline at postnatal days 3, 7, 17, and 30, and most were s acrificed 24 h later (n = 4 for each genotype at each age). Cerebellar volume, total volume and cell number for each deep cerebellar nucleus , densities for Purkinje and granule cells in the cerebellar cortex of lobules II, VI and IX, and the density of vacuolated Purkinje cells w ere all measured quantitatively. Cytoplasmic vacuolation provided an i ndication of bilirubin toxicity and was never observed in the Nj contr ol rats. Vacuolated Purkinje cells were first observed in jj-saline ra ts at 18 days and were found only in the more anterior lobules of the cerebellum (II and VI). By contrast, vacuolated Purkinje cells were ob served in jj-sulfa rats al both 4 and 8 days, but only in the most pos terior cerebellar lobule (IX). In all older jj rats, the decline in va cuolation was accompanied by significant necrosis and resorption of th e Purkinje cells in the anterior lobules. Since the Purkinje cells in the posterior lobules are the first to differentiate in the cerebellum and are resistant to bilirubin toxicity in jj-saline rats, the result s support the presence of a critical period when elevated brain biliru bin may be most toxic to neuronal development. The findings suggest th at neurons undergoing differentiation al the lime of bilirubin exposur e are most susceptible to cell death, while cells that are slightly mo re or slightly less mature may show only transient changes.