Reelin mutant mice as animal model of major neurobehavioural syndromes: relevance of gene-environment interaction

The identification of genes of susceptibility to major neuropsychiatric disorders (including autism and schizophrenia) has allowed the creation of mouse models with genetic characteristic of human disease. The study of behaviour, which is the ultimate output of brain function, plays a crucial role in this context: behavioural phenotype of genetically modified mice provides indeed functional information hardly detectable using neurobiological evaluations alone. Reelin and its codifying gene have been identified as important vulnerability factors to major neurobehavioural disorders, and mouse models carrying spontaneous gene mutations (partially or complete) have been used. In particular, we focused on mice which expresse a haploinsufficiency of reelin gene and display a mild phenotype. As starting point, a detailed characterization of the early behavioural communicative and motor responses of heterozygous reeler mice from soon after birth allowed us to evidence alterations in the developmental trajectories of specific behaviours (Chapter 2). Particular attention was devoted to the early phases of development by means of experimental protocols that take into account the practical constraints imposed by the peculiar physiological and behavioural responses of an immature mouse. Deviations from the age-dependent onset of normal response patterns and an overall delay in neurodevelopment were highlighted in heterozygous (Hz) reeler mice. In particular, a general increment in the expression of ultrasonic emissions, and a delayed profile of vocalizations and motor coordination were observed. Furthermore, a qualitative analysis of mouse pups vocal repertoire was performed that evidenced an ontogenetic delay and a restricted use of different vocal categories by mutant mice. The second aim of this thesis was to exploit the neurobehavioural characterization of heterozygous reeler mice to evaluate the interplay between mutation in reelin gene with two different environmental factors. In Chapter 3 are reported the behavioural and neurobiological outcomes across the lifespan on Hz and Wt mice of single 17-beta-estadiol brain inoculation in neonatal phase. In Chapter 4, the short-term behavioural and brain molecular effects of ripetute nicotine injections during adolescence are reported in Hz and Wt mice. Further, in Chapter 5 motivation to nicotine self consumption during adolescence were evaluated as well as its long-term behavioural (cognitive) and brain molecular (expression of reelin and GAD 67 genes) effects in adulthood as a function of juvenile nicotine exposure. Although these two strategies differ from several points of view (e.g. time of exposure: early infancy vs adolescence; environmental variable: estradiol vs nicotine), both were supposed to mimick the role of specific risk or protection factors which have been involved in the etiology of major neurobehavioural symptoms. The results revealed that, in spite of their differences, both estrogen and nicotine attenuated some of the behavioural as well as neurobiological abnormalities in heterozygous reeler mice, thus suggesting that reelin gene and protein may represent a pharmacological target aimed to the development of innovative therapeutic strategies.