Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice

The pituitary adenylate cyclase activating polypeptide (PACAP) type I recep tor (PAC1) is a G-protein-coupled receptor binding the strongly conserved n europeptide PACAP with 1000-fold higher affinity than the related peptide v asoactive intestinal peptide. PAC1-mediated signaling has been implicated i n neuronal differentiation and synaptic plasticity. To gain further insight into the biological significance of PAC1-mediated signaling in vivo, we ge nerated two different mutant mouse strains, harboring either a complete or a forebrain-specific inactivation of PAC1. Mutants from both strains show a deficit in contextual fear conditioning, a hippocampus-dependent associative learning paradigm. In sharp contrast, am ygdala-dependent cued fear conditioning remains intact. Interestingly, no d eficits in other hippocampus-dependent tasks modeling declarative learning such as the Morris water maze or the social transmission of food preference are observed. At the cellular level, the deficit in hippocampus-dependent associative learning is accompanied by an impairment of mossy fiber long-te rm potentiation (LTP). Because the hippocampal expression of PAC1 is restri cted to mossy fiber terminals, we conclude that presynaptic PAC1-mediated s ignaling at the mossy fiber synapse is involved in both LTP and hippocampus -dependent associative learning.