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Rett syndrome (RTT) is a neurodevelopmental disorder, primarily affecting girls. RTT causes severe cognitive, social, motor and physiological impairments and no cure currently exists. The discovery of a monogenic origin for RTT and the subsequent generation of RTT mouse models provided a major breakthrough for RTT research. Although the characterization of these mutant mice is far from complete, they recapitulate several RTT symptoms. This review provides an overview of the behavioural domains so far investigated in these models, including the very few mouse data concerning the developmental course of RTT. Both clinical and animal studies support the presence of early defects and highlight the importance of probing the presymptomatic phase for both the precocious identification of biomarkers and the early assessment of potential therapies. Preclinical evaluations of pharmacological and nonpharmacological interventions so far carried out are also illustrated. In addition, genetic manipulations are reported that demonstrate rescue from the damage caused by the absence of the methyl-CpG-binding protein 2 (MeCP2) gene even at a mature stage. Given the rare occurrence of RTT cases, transnational collaborative networks are expected to provide a deeper understanding of aetiopathology and the development of new therapeutic approaches.

We examined long-term behavioural effects of neonatal lesions of the cholinergic basal forebrain obtained by intracerebroventricular injections of 192 IgG saporin (192 IgG-Sap). Five-month-old Wistar male rats (injected with 192 IgG-Sap or phosphate-buffered saline on postnatal day 7) were tested using operant chambers with two nose-poking holes, delivering one food pellet immediately or five pellets after a delay. The length of delay progressively increased over days (from 0 to 100 s). When compared with controls, 192 IgG-Sap rats showed a slight preference for smaller immediate over larger delayed rewards, thus indicating elevated intolerance to delay (i.e. more impulsivity). Sibling animals were tested in a computerized radial maze (baited vs. nonbaited arm procedure). 192 IgG-Sap rats appeared slower than controls in accomplishing the task. The neonatal 192 IgG-Sap lesion did not alter cortical levels of serotonin and/or its metabolites, but induced a marked cortical cholinergic loss. Our data suggest that a prolonged basal forebrain cholinergic hypofunction produces (i) an impairment in cognitive performances that is detectable only when highly complex tasks are used; (ii) a slight enhancement of the impulsive behavioural profile. This animal model may thus be useful to investigate some cognitive deficits and other secondary symptoms seen in Alzheimer's disease.