Social and learning deficit, increased aggression and seizure susceptibility in otr null mice is reversed by ot/avp treatment: a model of autism
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Data di Pubblicazione:
2010
Citazione:
Social and learning deficit, increased aggression and seizure susceptibility in otr null mice is reversed by ot/avp treatment: a model of autism / A. Finardi, A. Donzelli, V. Capurro, D. Braida D, K. Nishimori, B. Chini, M. Sala. ((Intervento presentato al convegno Riunione nazionale dottorandi e borsisti italiani in neuroscienze e materie affini tenutosi a Busto Arsizio nel 2010.
Abstract:
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
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
A. Finardi, A. Donzelli, V. Capurro, D. Braida D, K. Nishimori, B. Chini, M. Sala
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