Impairment of Mossy Fiber Long-Term Potentiation and Associative Learning in Pituitary Adenylate Cyclase Activating Polypeptide Type I Receptor-Deficient Mice

Abstract

The pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (PAC1) is a G-protein-coupled receptor binding the strongly conserved neuropeptide PACAP with 1000-fold higher affinity than the related peptide vasoactive intestinal peptide. PAC1-mediated signaling has been implicated in neuronal differentiation and synaptic plasticity. To gain further insight into the biological significance of PAC1-mediated signaling in vivo, we generated 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, amygdala-dependent cued fear conditioning remains intact. Interestingly, no deficits 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-term potentiation (LTP). Because the hippocampal expression of PAC1 is restricted to mossy fiber terminals, we conclude that presynaptic PAC1-mediated signaling at the mossy fiber synapse is involved in both LTP and hippocampus-dependent associative learning.

A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth

“…[16][17][18][19][20][21][22][23] In accordance with previous observations, 30 in situ hybridization of adult rat brains showed intense expression of PAC 1 mRNA in the periglomerular and granule cells of the olfactory bulb, the granule cells of the dentate gyrus, the cerebral cortex (especially layer II) and many regions of the hypothalamus (Figure 3a and b). Thus, prominent signals for both DBZ and PAC 1 transcripts were detected in the dentate gyrus (Figure 3b upper panels).…”

“…DISC1 is a possible candidate gene for schizophrenia that is predominantly expressed in certain brain [18][19][20][21][22][23] was indicated by our present findings. DISC1 has been proposed to be a multifunctional protein that interacts with multiple proteins of the centrosome and cytoskeletal system at distinct domains.…”

“…21 Recently, we demonstrated that Adcyap1 À/À mice lacking PACAP exhibit marked behavioral abnormalities and other changes. [18][19][20] Adcyap1 À/À mice are born in the expected Mendelian ratio, but show a high early mortality rate before weaning.…”

“…[18][19][20] PAC 1 receptor-deficient mice also demonstrated an increase of locomotor activity, reduced anxiety-like behavior and abnormal social behavior, as well as impairment of hippocampal LTP. [21][22][23] These observations indicate that PACAP signaling mediated via the PAC 1 receptor has a critical role in the development and/or functioning of neural pathways and suggest the potential clinical relevance of PACAP signaling dysfunction to neuropsychiatric disorders.…”

Active zones for presynaptic plasticity in the brain

“…They found that Rab3A knockout mice present no detectable defect in learning and memory. These data indicate that deficient mossy fiber LTP is probably not the reason for the spatial learning defect of RIM1-alpha mutants, in agreement with other studies in mutant mice lacking Rab3A 169 or with defects in PKA activity Huang et al; 170 see also Villacres et al, 171 Wu et al 172 and Otto et al 173 In order to investigate whether the decrease in Pr could be the cause of the behavioral phenotype, Powell et al included in the analysis synaptotagmin 1 R233Q knockin mice to compare them with RIM1-alpha mutants. Synaptotagmin 1 is a Ca 2 þ sensor for fast and synchronous exocytosis.…”