title: Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism.
abstract: 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.
authors.affiliation: Department of Pharmacology, Chemotherapy and Medical Toxicology, Università degli Studi di Milano, Milan, Italy.
authors.forename: Mariaelvina
authors.initials: M
authors.lastname: Sala
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.forename: Daniela
authors.initials: D
authors.lastname: Lentini
authors.forename: Marta
authors.initials: M
authors.lastname: Busnelli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bulgheroni
authors.forename: Valeria
authors.initials: V
authors.lastname: Capurro
authors.forename: Annamaria
authors.initials: A
authors.lastname: Finardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Donzelli
authors.forename: Linda
authors.initials: L
authors.lastname: Pattini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nishimori
authors.forename: Marco
authors.initials: M
authors.lastname: Parenti
authors.forename: Bice
authors.initials: B
authors.lastname: Chini
mesh_terms: D000374:Aggression / Q000187:drug effects* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism / Q000494:pharmacology*; D001321:Autistic Disorder; D001345:Autoradiography; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010121:Oxytocin / Q000378:metabolism / Q000494:pharmacology*; D018045:Receptors, Oxytocin / Q000235:genetics*; D012640:Seizures / Q000235:genetics / Q000503:physiopathology*; D012919:Social Behavior
chemical_list: D018045:Receptors, Oxytocin; D001127:Arginine Vasopressin; D010121:Oxytocin