Map kinase (MAPK) signaling is important for the induction and expression of certain forms of long-term potentiation (LTP). Using mice expressing a dominant negative Rap1B transgene, we found that in the hippocampus MAPK is modulated by Rap1B (Morozov et al., 1999, SFN abstracts, V22, 255.1). We have now used these mice to examine the contribution of Rap1B to the induction of LTP. Mutant mice have deficient LTP induction after either forskolin or theta frequency stimulation in area CA1 of the hippocampus. Inhibition of MAPK with UO126 (0.02 mM) causes a similar LTP induction deficit in wild-type mice, but does not further reduce LTP in mutant mice. Complex spike firing during theta frequency tetanization is reduced in mutant mice and during perfusion of UO126, suggesting that inhibition of the RAP1B/MAPK pathway decreases neuronal excitability. A corresponding decrease in excitability is also observed with whole-cell recordings from CA1 pyramidal neurons. The early LTP deficits and reduction in complex spi...