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 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.
Otto
C
C
Divisions of Molecular Biology of the Cell and Experimental Pathology, German Cancer Research Center, 69120 Heidelberg, Germany.
Kovalchuk
Y
Y
Wolfer
D P
DP
Gass
P
P
Martin
M
M
Zuschratter
W
W
Gröne
H J
HJ
Kellendonk
C
C
Tronche
F
F
Maldonado
R
R
Lipp
H P
HP
Konnerth
A
A
Schütz
G
G
D000818:Animals; D001245:Association Learning / Q000502:physiology*; D001362:Avoidance Learning / Q000502:physiology; D003463:Cues; D004597:Electroshock; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012919:Social Behavior
C495504:Adcyap1r1 protein, mouse; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone