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The Journal of Neuroscience, October 6, 2004, 24(40):8786-8795; doi:10.1523/JNEUROSCI.1910-04.2004

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Behavioral/Systems/Cognitive
Altered Social Behavior in Pituitary Adenylate Cyclase-Activating Polypeptide Type I Receptor-Deficient Mice

Arnaud Nicot,¹ Timothy Otto,² Philippe Brabet,³ and Emanuel M. DiCicco-Bloom¹

¹Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, ²Department of Psychology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, and ³Institut National de la Santé et de la Recherche Médicale U583, Institut des Neurosciences de Montpellier, Centre Hospitalier Universitaire Saint-Eloi, 34295 Montpellier, France

The olfactory bulb plays a critical role in odor discrimination and in processing olfactory cues controlling social behavior in mammals. Given that the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1) is highly expressed in the olfactory bulb, we examined its role in regulating olfaction and social investigation. We found that olfactory detection of nonsocial stimuli was similar in PAC1-deficient mice and wild-type (WT) littermates. In contrast, PAC1-deficient mice displayed markedly abnormal social behaviors. PAC1-deficient mice exhibited a faster decrease in social investigation after repeated exposure to social cues or ovariectomized female urine compared with WT mice. Moreover, PAC1-deficient females exhibited delayed affiliative behavior when housed with novel males, and PAC1-deficient males displayed excessive sexual mounting toward both females and males as well as reduced aggression and increased licking and grooming toward intruder males. In aggregate, these results uncover PAC1 signaling as an important factor in the development and/or functioning of neural pathways associated with pheromone processing and the regulation of social interactions in mice. In turn, these studies raise the potential clinical relevance of PACAP signaling dysfunctions in neuropsychiatric disorders characterized by social reciprocity impairments such as autism spectrum disorders.

Key words: behavior; peptide; olfaction; sex; receptor; memory

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Received March 11, 2004; revised August 27, 2004; accepted August 27, 2004.

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