Pharmacologic Rescue of Impaired Cognitive Flexibility, Social Deficits, Increased Aggression, and Seizure Susceptibility in Oxytocin Receptor Null Mice: A Neurobehavioral Model of Autism Mariaelvina Sala, Daniela Braida, Daniela Lentini, Marta Busnelli, Elisabetta Bulgheroni, Valeria Capurro, Annamaria Finardi, Andrea Donzelli, Linda Pattini, Tiziana Rubino, Daniela Parolaro, Katsuhiko Nishimori, Marco Parenti, and Bice Chini Background: Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt -/- ) and the OT receptor null mice (Oxtr -/- ) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization. Methods: Oxtr -/- mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr +/+ and Oxtr -/- mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography. Results: Oxtr -/- mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABA– ergic versus total presynapses in hippocampal neurons of Oxtr -/- mice. Conclusions: Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr -/- adult animals. The Oxtr -/- mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention. Key Words: Animal model, autism spectrum disorders, cognitive flexibility, oxytocin, seizures, vasopressin O xytocin (OT) and vasopressin (AVP) neuropeptides play a key role in the control of several cognitive, social, and neu- roendocrine functions. In humans, they participate in the regulation of learning and memory and in emotional and social behaviors, including facial recognition and mind reading, trust, generosity, envy, and gloating (1). In rodents, a number of studies have reported their activities in maternal care, pair bonding, sexual behavior, social memory, anxiety and aggression, reward, learning, and memory (2–5). The key role of these neuropeptides in shaping the social brain (6) has prompted the investigation of the OT/AVP peptide/receptor system in human conditions in which social behavior is impaired, such as autism spectrum disorders (ASDs) (7,8). Despite the scarce genetic evidence supporting the involvement of the OT/AVP pep- tide/receptor genes in the pathogenesis of ASDs (6), pivotal clinical trials have shown that intranasal or intravenous administration of OT improves the autistic symptoms, thus indicating that OT system can represent a valid therapeutic target (9 –12). In the case of an impairment in the neuronal circuitries shaping the social brain, occurring during early development for a genetic cause and/or an environmental assault, the manipulation of the OT/AVP system could represent a way to restore the impaired brain connections, hence improving the symptoms. OT has been shown to modulate synaptic plasticity not only in the newborn (13), in which it protects the brain from ischemic injuries, but also in adult animals, as in the adult hippocampus during motherhood (14). To test the effects of modulating the OT/AVP system in animals displaying social deficits, we employed a mouse line in which OT neurotransmission is abolished by knocking out the OT receptor gene (Oxtr -/- )(15). The OT receptor, which belongs to the G pro- tein coupled receptor superfamily, is the main target of OT within the brain, whereas AVP binds to and activates the highly homolo- gous V1a and V1b receptor subtypes. Oxtr -/- animals have been previously reported to display a severe impairment in social recog- nition, revealed by deficits in nurturing and social memory; reduced ultrasonic vocalization of pups upon separation from mother, re- flecting a reduced distress to social isolation and/or a communica- tion deficit; and increased aggression (15). Surprisingly, no defects in learning or spatial memory have been reported thus far despite the well-known effects of OT on these cognitive functions (2,4). Although OT and AVP do not seem to affect the learning phase of From the Department of Pharmacology, Chemotherapy and Medical Toxi- cology (MS, DB, MB, VC, AF, AD), Università degli Studi di Milano, Milan; Department of Experimental Medicine (DL, MP), University of Milano- Bicocca, Monza; Institute of Neuroscience (MB, EB, BC), Consiglio Nazi- onale delle Ricerche, Milan; Department Bioengineering (LP), Politec- nico di Milano, Milan; Department of Structural and Functional Biology (TR, DP), University of Insubria, Busto Arsizio, Varese, Italy; and Depart- ment Molecular and Cell Biology (KN), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan. Address correspondence to Bice Chini, M.D., Ph.D., CNR, Institute of Neuro- science, via Vanvitelli 32, 20143, Milano, Italy; E-mail: b.chini@in.cnr.it. Received May 7, 2010; revised Dec 15, 2010; accepted Dec 15, 2010. BIOL PSYCHIATRY 2011;69:875– 882 0006-3223/$36.00 doi:10.1016/j.biopsych.2010.12.022 © 2011 Society of Biological Psychiatry