Rett syndrome (RTT) is a progressive non degenerative neurodevelopmental disease affecting mainly females, with an incidence of 1 out 10.000 newborn girls. Its symptomatology is very variable and may include: motor deficits, intellectual disability, cardiorespiratory alterations and epilepsy, among other alterations. RTT diagnosis is complex and mainly based on clinical evaluations. All patients apparently develop normally until approximately the first year of life. Then, a developmental stagnation occurs, followed by a regression period in which patients lose acquired skills. In most cases, RTT is due to loss-of-function mutations in the MECP2 gene, which encodes the methyl-CpG-binding protein 2 (MeCP2), a widespread chromatin organizer that controls the transcription of hundreds of genes. Even if experiments performed in a mouse model showed a reversion of RTT-like phenotypes after the re-expression of murine Mecp2, at present there is no a cure for RTT. Pharmacological and physical therapies are the only available techniques to alleviate RTT symptomatology. Regarding drugs, all treatments used on RTT patients are used only for specific symptoms. Since monoaminergic systems are downregulated in both RTT patients and mouse models, antidepressants have been proposed as candidate drugs to treat this disease. Among them, mirtazapine (MTZ) has showed an excellent safety profile through years and the ability to rescue several behavioural, physiological and neuroanatomical phenotypes in a male mouse model of RTT. The present project aimed to complete and to extend these results, as well as to find some mechanisms of action of MTZ. To do this, we used Mecp2tm1.1Bird female mice, a RTT model with a verified face validity, and treated them at different ages and for different durations. First, we verified the safety of MTZ, as we did not observe any adverse effects, even when we treated young female mice with a high dosage of MTZ for one month. Second, we found several improvements in motor, somatosensory and cognitive domains. In one case, we were able to propose a mechanism for the behavioural rescue, as MTZ normalized parvalbumin expression in a related brain area. Results in female mice were completed by a retrospective analysis of a heterogeneous cohort of adult RTT patients that had been treated with MTZ for long periods. Only 2 out 11 patients showed adverse effects and were discontinued, while others showed an improvement of several clinical features in the motor domain, as well as in multiple behavioural alterations. In summary, results obtained in this thesis strongly supports MTZ as a promising treatment for RTT. They represent a robust proof-of-concept and will constitute the base of a dossier aimed to obtain the ethical authorization to initiate a randomized clinical trial. In this way, it will be possible to verify whether MTZ can effectively alleviate RTT symptomatology and, thus, improve quality of life of affected people and their families.
