Cellular priori protein (PrPc) is a saturable, specilic, high-affinity receptor for laminin (Ln), an extracellular matrix protein which has been shown to mediate neuronal migration and differentiation. PrPc binding site resides in a carboxyl-terminal decapeptide from the gamma1 chain (RNIAEIIKDI) of the Ln molecule. Objectwe: the aim of this study was to compare the Lnand RNIAEIIKDI-mediated neurite outgrowth in cultured hippocampal neurons from rat and wild-type I PrPc-null moue brains. We further evaluated the effect of the inhibition of PrPc by specific antibodies on neuritogeneais of rat and mouse nw~ons. Methods: Primary neuronal cultures were obtamed from embrionic rat and mouse brains. The hippocampal tissue was dissociated into a single cell wspensmn and plated on Ln or RNIAEIIKDI substrate. After cell adhesion, antibodies raised against PrPc (and the respective non-immune control sera) were added to culture medium. Culturer of rat and mouse neurons were incubated for I2 or 24 hours respectively, after which cella were fixed, stained and counted. The percentage of neumns with processes longer than 4 times the length of the respective cell body was used to ascertain neurite outgrowth withm different treatment conditions. Results: The Inhibition of neuritogenesis of rat hippocampal neurons by anti-PrPc serum was 50% when plated on Ln and 80% on RNIAEIIKDI substrate. The percentage of neurites amongst untreated wild-type mouse neurons was 40% when plated on Ln and 20% on RNIAEIIKDI; anti-PrPc treatment reduced such percentages to 20% and 5% rapectively. Cultures of PrPc null neurons had 20% of neurites on Ln, and such value was unchanged by anti-PrPc treatment. A very alnaIl number of neurites was observed in cells from PrPc null mice plated on RNIAEIIKDI, and no additional inhibitory effect was determined by anti-PrPc. Conclusions: PrPc is involved in Ln-induced neuritogenesis in normal mouse and rat neurons and this pathway is abrogated in PrPc null mice neurons and by the use of anti-PrPc serum. These results suggest a physiologic role for PrPc in neuronal plasticity.