[P1.32]: Wnt/beta‐catenin signalling at the dorsal diencephalic‐telencephalic boundary is altered in ( Gli3 Xt/Xt ) mutants

Rett syndrome (RTT), a leading cause of mental retardation, is a severe monogenic neurodevelopmental disorder affecting primarily girls, characterized by profound alterations of motor, behavioural and cognitive capacities. In RTT, cognitive deficits and neuropathological signs indicate that genes involved in dendritic and axonal formation might preferentially be affected in Mecp2 deficiency. Rho GTPases are crucial molecules in neuronal plasticity and cognition, as confirmed by their role in non-syndromic mental retardation. Recently, the activation of cerebral Rho GTPases induced by the bacterial protein CNF1 has been reported to improve learning and memory in wt mice, reshape the actin cytoskeleton, enhance neurotransmission and synaptic plasticity. We investigated the capacity of CNF1 icv administration to contrast some of the motor and cognitive features of the RTT phenotype in fully symptomatic Mecp2-308 mice. An amelioration of forelimb motor coordination capacities in a nest-material manipulation task was found. A specific impairment in this task had been previously reported in Mecp2-308 mice possibly corresponding to the apraxia of hand use seen in RTT patients. Abnormalities in circadian motor activity have also been reported in RTT mice. After icv CNF1 inoculation, mutant mice reached a wt-like profile of circadian locomotor cyclicity. An improved profile was also evident in a cognitive fear-conditioning task: the deficit exhibited by mutant mice was efficaciously contrasted by CNF1 administration. These findings in mice highlight the possibility that CNF1 might have a therapeutic potential against the severe impairment of cognitive and adaptive skills characterizing fully RTT symptomathology. Supported by Italy-USA Program on Rare Disease “X-linked or autosomal rare mental retardation syndromes”; by ERARE-EuroRETT Network to GL.