NEW PHARMACOLOGICAL TOOLS FOR AUTISM RESEARCH: OXYTOCIN RECEPTOR MUTANT MICE AND ZEBRAFISH AS NEUROBEHAVIOURAL MODELS
Tesi di Dottorato
Data di Pubblicazione:
2011
Citazione:
NEW PHARMACOLOGICAL TOOLS FOR AUTISM RESEARCH: OXYTOCIN RECEPTOR MUTANT MICE AND ZEBRAFISH AS NEUROBEHAVIOURAL MODELS / V. Capurro ; tutor: Mariaelvina Sala ; direttore della scuola: Alberto E. Panerai. Universita' degli Studi di Milano, 2011 Jan 17. 23. ciclo, Anno Accademico 2010. [10.13130/capurro-valeria_phd2011-01-17].
Abstract:
Autism is a neurodevelopmental disorder which is characterized by severe and pervasive impairment in reciprocal socialization, qualitative impairment in communication and repetitive or stereotyped behaviour associated to resistance to change. Oxytocin (OT) is a peptidic hormone best known for its role in lactation and parturition. Recently, it has been also shown by several studies involving different lines of knock-out mice to play an important role in the central nervous system (CNS) by acting on the regulation of social, emotional, aggressive behaviour and on learning and memory. Furthermore, prosocial effects following OT administration in humans have been shown. The link between OT and autism has already been traced in preliminary clinical studies as autism affected patients received a beneficial outcome from treatment with OT. Pharmacokinetic (very short half-life), pharmacodynamic (unspecific binding to vasopressin (AVP) receptors) properties and the presence of peripheral side effects of OT, though, make this peptide an unsuitable target for a future clinical use. It is important, in this perspective, to characterize specific animal models in order to validate the use of OT analogs with more suitable characteristics for preclinical research.
To this end, a characterization of the behavioural phenotype of OTR knock-out mice (OTR-/-) and heterozygous littermates (OTR+/-) in comparison with their wild type counterparts (OTR+/+) has been carried out. General home cage behaviour, sensory, motor abilities and emotional behaviour were not affected by the altered genotype. Interestingly, both and OTR+/- and OTR-/- mice exhibited a significant social impairment as quantified in both the sociability and social novelty tests. Furthermore, OTR-/- mice displayed much higher levels of aggression when facing a stranger mouse as a higher number of attacks and tail rattlings has been registered in the neutral cage paradigm. Moreover, when tested in the reversal phase of a T-maze task for their cognitive flexibility, OTR-/- showed a profound impairment in responding to the changes applied in their established routine. All in all, the OTR mutant mouse model provides full range autism-related aberrant behaviours, displaying social impairments, altered aggressive behaviour, a strong resistance to change and stereotyped behaviour. Mechanisms underlying the aberrant phenotype revealed by mutant mice were investigated through autoradiographic binding experiments for both OTR and vasopressin 1A receptor (V1aR) distribution. In addition, pharmacological treatments with OT, AVP and V1aR antagonist SR49059 were done. Binding experiments were carried out in specific brain areas known to exert a key role in integrating the processing of olfactory information that is crucial to regulate social and emotional behaviour in rodents. OTR-/- animals displayed an almost undetectable OTR binding in all tested areas. Furthermore, a slight compensatory up-regulation of V1aR in the hippocampus and a significant down-regulation of the V1aR expression in the anterior olfactory nucleus, amygdala, ventral pallidum and lateral septum were found. As for heterozygous mutants their phenotype appeared as halfway between the wild type and knock out counterparts for OTR binding sites and V1aR binding has been subjected to a slight reduction in ventral pallidum and anterior olfactory nucleus only. Hence, the previously mentioned aberrant behavioural phenotype displayed by OTR mutant mice could be due to an altered OT/AVP receptors concentration in crucial brain areas. Interestingly, intracerebroventicular treatment with both OT and AVP (0.5ng/mouse) in mutant mice was able to rescue the impairment shown in all behavioural tasks. Furthermore, pre-treatment with V1aR antagoni
Tipologia IRIS:
Tesi di dottorato
Keywords:
autism ; oxytocin;
Elenco autori:
V. Capurro
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