Receptor-associated protein appears to play an important role in low-density lipoprotein receptor-related protein trafficking. Since ligands for the low-density lipoprotein receptor-related protein have been implicated in Alzheimer's disease and normal functioning of this protein is indispensable for central nervous system development, deficient receptor-associated protein expression may result in central nervous system alterations. In this study, receptor-associated protein knockout mice were behaviorally tested and nervous system integrity was assessed via in situ hybridization and immunocytochemical/laser confocal microscopy methods. Receptor-associated protein knockout mice were found to be cognitively impaired in the Morris water maze compared to controls. In wild-type mice, the receptor-associated protein was found to be highly co-expressed with somatostatin in hippocampal and neocortical inhibitory neurons. Receptor-associated protein knockout mice, however, showed a significant decrease in number of somatostatin-expressing neurons of the CA1 region and somatostatin expression within these neurons. The decreased number of somatostatin neurons significantly correlated with cognitive impairment observed in the receptor-associated protein knockout mice. These results suggest a novel role for receptor-associated protein in modulating the functioning of somatostatin-producing neurons. Furthermore, this has implications for Alzheimer's disease pathogenesis, in which altered regulation of both somatostatin and the known low-density lipoprotein receptor-related protein ligands are a consistent finding.