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Modulation of Rhogtpases by the Bacterial Protein CNF1 Improves the Neurobehavioural Phenotype in a Mouse Model of Rett Syndrome

Thursday, 2 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
B. De Filippis, A. Fabbri, R. Canese, L. Ricceri, F. Malchiodi-Albedi, C. Fiorentini and G. Laviola, Istituto Superiore di Sanità, Rome, Italy
Background: RhoGTPases are crucial molecules in neuronal plasticity and cognition, as confirmed by their role in non-syndromic mental retardation. Activation of brain RhoGTPases by the bacterial Cytotoxic Necrotizing Factor 1 (CNF1) reshapes the actin cytoskeleton and enhances neurotransmission and synaptic plasticity in mouse brains. Recently, Rho GTPases signaling pathways have been suggested to be involved in the pathophysiology of a clinical variant of Rett syndrome (RTT). Classified together with autism into the DSM-IV in the group of pervasive developmental disorders, RTT is a rare neurodevelopmental disorder primarily affecting girls with a prevalence of 1:10,000 births, for which no effective therapy is available. Objectives: We evaluated whether pharmacological interventions targeting RhoGTPases may be an effective therapeutic strategy for RTT. Methods: To this aim, we performed a single CNF1 intracerebroventricular (icv) inoculation in a RTT mouse model, which expresses a truncated form of the MeCP2 gene (MeCP2-308 mice). Fully symptomatic MeCP2-308 male mice were subsequently evaluated in a battery of tests specifically tailored to detect RTT-related impairments. At the end of behavioral testing, brain sections were immunohistochemically characterized. Magnetic resonance imaging (MRI) and spectroscopy (MRS) were also applied to assess morphological and metabolic brain changes. Results: The CNF1 administration markedly improved the behavioral phenotype of MeCP2-308 mice. CNF1 also dramatically reversed the evident signs of atrophy in astrocytes of mutant mice and restored wt-like levels of this cell population. CNF1-induced brain metabolic changes detected by MRS analysis involved markers of glial integrity and bioenergetics, and point to improved mitochondria functionality in CNF1-treated mice. Conclusions: These results clearly indicate that modulation of brain RhoGTPases by CNF1 may constitute a totally innovative therapeutic approach for RTT and, possibly, for other neurodevelopmental disorders.
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