Hirschsprungs disease is a congenital condition characterised by the absence of enteric ganglia and is often associated with neurological abnormalities.This disease in rats,as in human,can be caused by endothelin receptor B (EDNRB) mutation.Little is known about the effects of EDNRB mutation on brain development.In this study,we investigated the changes in cell proliferation and death in the brain of the spotting lethal (si) rat,which carries a deletion in the EDNRB gene.Proliferating cells in wild-type (+/+) and homozygous mutant (sl/sl) rats were labelled by intraperitoneal injection of 5-bromo-2-deoxyuridine (BrdU) at postnatal day 2.The density of BrdU-labelled cells in the CA1 and CA3 regions of the hippocampus and dentate gyrus of sl/sl rats was significantly reduced compared to the corresponding regions of +/+ rats.The effect of EDNRB mutation on neural cell death was examined by using terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay (TUNEL).This showed that the density of apoptotic cells in the hippocampus of sl rats (16.4 ± 5.5/mm2,mean ± SEM) was significantly more increased than +/+ rats (2.9 ± 0.7/mm2).The expression of brain derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured with standard ELISA in the hippocampus,but no difference was revealed between genotypes.These results suggest that ENDRB mutation reduces neural proliferation and increases cell death in the hippocampus and dentate gyrus of the spotting lethal rat,and that these effects are independent of changes in the expression of BDNF and GDNF.Our findings will lead to a better understanding of cellular changes in the brains of Hirschsprungs disease patients with congenital EDNRB mutation.