Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism.

Background: Oxytocin (OT) has been suggested as a treatment to improve social behaviour in autistic patients. Accordingly, the OT (Oxt-/-) and the OT receptor null mice (Oxtr-/-) display autistic-like deficits in social behaviour, increased aggression and reduced ultrasonic vocalization. Methods: Oxtr-/- mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression and seizure susceptibility. Since vasopressin (AVP) and OT cooperate in controlling social behaviour, learning and aggression, they were tested for possible rescue of the impaired behaviours. Primary hyppocampal cultures from Oxtr+/+ and Oxtr-/- mouse embryos were established to investigate the balance between 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: (i) a resistance to change in a learned pattern of behaviour, comparable to restricted interests and repetitive behaviour in autism, and (ii) 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 GABAergic versus total pre-synapses 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 pharmacological intervention.