Article

2676 • The Journal of Neuroscience, March 4, 2009 • 29(9):2676 –2683

Behavioral/Systems/Cognitive

Vasopressin 1b Receptor Knock-Out Impairs Memory for Temporal Order
Loren M. DeVito,1 Rachael Konigsberg,1 Christine Lykken,1 Magdalena Sauvage,1 W. Scott Young III,2 and Howard Eichenbaum1
Center for Memory and Brain, Boston University, Boston, Massachusetts 02215, and 2Section on NeuralGene Expression, National Institute of Mental Health–National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892
1

Mice lacking a functional vasopressin 1b receptor (Avpr1b) display decreased levels of aggression and social memory. Here, we used Avpr1b-knock-out (Avpr1b / ) mice to examine whether an abnormality of this receptor results in specific cognitivedeficits in the domain of hippocampal function. Avpr1b / mice were deficient in sociability and in detecting social novelty, extending previous findings of impairment in social recognition in these mutants. Avpr1b / mice could recognize previously explored objects and remember where they were experienced, but they were impaired in remembering the temporal order of presentation of those objects.Consistent with this finding, Avpr1b / mice were also impaired on an object– odor paired associate task that involved a temporal discontiguity between the associated elements. Finally, Avpr1b / mice performed normally in learning a set of overlapping odor discriminations and could infer relationships among odors that were only indirectly associated (i.e., transitive inference), indicating intactrelational memory. The Avpr1b is expressed at much higher levels than any other part of the brain in the pyramidal cells of hippocampal CA2 area, a subfield of the hippocampus that has physiological and genetic properties that distinguish it from subfields CA1 and CA3. The combined results suggest that the Avpr1b, perhaps in CA2, may play a highly specific role in social behavior and episodic memory.Because schizophrenia and bipolar disorder are associated with a unique pathology in CA2 and impairments in both social behavior and episodic memory, this animal model could provide insights into the etiology of these disorders.

Introduction
The vasopressin 1b receptor (Avpr1b) plays an important role in the regulation of social behaviors (Wersinger et al., 2002). Mice with a selectivedeletion of Avpr1b (Avpr1b / ) are impaired in social recognition, conspecific aggression, and pregnancy block, also known as the Bruce effect (Wersinger et al., 2004, 2007, 2009). However, Avpr1b / mice display normal mating behavior, olfactory discrimination, prey recognition, and defensive aggression (Caldwell et al., 2008). In contrast to the deficits in social behavior, Avpr1b / mice have intactsensorimotor function, exploratory behavior, and spatial memory (Wersinger et al., 2002). The highest level of brain expression of Avpr1b is in the CA2 subfield of the dorsal hippocampus (Young et al., 2006). Although the structure, function, and physiology of hippocampal subfields CA1 and CA3 have been extensively studied (Leutgeb et al., 2004; Kesner et al., 2005), very little is known about thefunctional role of the transitional area CA2. Interestingly, schizophreReceived Nov. 12, 2008; revised Dec. 14, 2008; accepted Jan. 13, 2009. This work was supported by grants from the Conte Center for Schizophrenia Research–National Institutes of Health and by National Institute of Mental Health Intramural Research Program Grant Z01-MH-002498-20 (W.S.Y.). Thanks to Katherine O’Brien for assistancewith behavioral training, Will Sauls for skilled mouse husbandry and maintenance of the breeding colony, and Emily Shepard for genotyping. We also thank Dr. Norbert Fortin for comments on this manuscript. Correspondence should be addressed to Dr. Howard Eichenbaum, Center for Memory and Brain, Boston University, Boston, MA 02215. E-mail: hbe@bu.edu. DOI:10.1523/JNEUROSCI.5488-08.2009 Copyright ©...