Social and learning deficit, increased aggression and seizure susceptibility in otr null mice is reversed by ot/avp treatment: a model of autism

Background. Oxytocin (OT) and vasopressin (AVP) neuropeptides play a key role in the control of several cognitive, social and neuroendocrine functions. In humans, they are involved in the regulation of memory, emotional and social behaviours, including facial recognition and mind reading, trust, generosity, envy and gloating1. In rodents, several studies have reported their actions in maternal care, pair bonding, sexual behaviour, social memory, anxiety and aggression, reward, learning and memory2. Recent genetic studies in humans suggest the involvement of OT and AVP in autism3. Aim. 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 (OTR-/-)4. Behavioural and electroencephalographic profile of OTR-/- in comparison to OTR+/+ mice was also studied. Methods. Social behaviour was assessed by social approach to stranger mouse and the preference for social novelty; aggression was evaluated in a neutral cage introducing an intruder and spatial learning and cognitive flexibility with a T-maze task. Electroencefalographic profile was evaluated in freely moving awake mice either as basal electrical activity or as susceptibility to pentylenetetrazol-induced seizures. Results. Our findings indicate that OTR-/- mice resulted to be impaired in social recognition, as they preferred staying alone rather than investigating a novel mouse. They were also impaired in social memory having no interest in exploring an unfamiliar mouse. Cognitive flexibility was also disrupted, as OTR-/- mice needed more days to reach the criterion when the reinforcer position was switched in the Tmaze task. An increased aggression was shown only in mutant mice. Intracerebroventricular injection (0.5 ng/mouse) of both OT and AVP fully rescued all the observed behavioural impairments. Co-treatment with SR 49059, the AVP V1a receptor subtype antagonist, significantly blocked the improvement induced by both peptides. We found also that pentylenetetrazol (30 mg/kg i.p.) induced tonic-clonic seizures in OTR-/- while only myoclonic jerks in OTR+/+ mice. A reduced thresholds latency to the first seizure was observed in mutant mice. Conclusions. Our behavioural findings indicate that the OTR null mouse is recapitulative of all the core symptoms of autism, which could be rescued by OT or AVP administration, representing a very valuable animal model to investigate the neuroanatomical and synaptic abnormalities underlying autism symptoms and to identify new pharmacological strategies. Furthermore, the greater susceptibility to seizures observed in OTR mutant mice suggests a link between epilepsy and OT/AVP system in autism sprectal disorders as approximately 30% of children with autism have epilepsy5 and 30% of children with epilepsy, have autism6. References: 1. Macdonald K and Macdonald TM (2010) Harv Rev Psychiatry 18(1):1-21 2. McEwen BB (2004) Adv Pharmacol 50:1-50, 655-708 3. Donaldson ZR and Young LJ (2008) Science 322(5903):900-4 4. Takayanagi Y et al. (2005) Proc Natl Acad Sci U S A 102:16096 5. Tuchman R and Rapin I (2002) Lancet Neurol 1:352-8 6. Clarke DF et al. (2005) Epilepsia 46 :1970-7