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The Journal of Neuroscience, August 1, 2001, 21(15):5520-5527

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

Christiane Otto¹, Yury Kovalchuk³, David Paul Wolfer⁴, Peter Gass^{1, 5}, Miguel Martin⁶, Werner Zuschratter⁷, Hermann Josef Gröne², Christoph Kellendonk^{1, 8}, François Tronche¹, Rafael Maldonado⁶, Hans-Peter Lipp⁴, Arthur Konnerth³, and Günther Schütz¹

Divisions of ¹ Molecular Biology of the Cell and ² Experimental Pathology, German Cancer Research Center, 69120 Heidelberg, Germany, ³ Department of Physiology, Ludwig Maximilians University München, 80802 München, Germany, ⁴ Institute of Anatomy, University of Zürich, 8057 Zürich, Switzerland, ⁵ Central Institute of Mental Health, 68159 Mannheim, Germany, ⁶ Department of Neuropharmacology, University Pompeu Fabra, 08003 Barcelona, Spain, ⁷ Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany, and ⁸ Center for Neurobiology and Behavior, Howard Hughes Medical Institute, Columbia University, New York, New York 10032

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.

Key words: PACAP type I receptor; knock-out mice; fear conditioning; synaptic plasticity; LTP; mossy fiber

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21155520-08$05.00/0

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