Modulation of RhoGTPases Improves the Behavioral Phenotype and Reverses Astrocytic Deficits in a Mouse Model of Rett Syndrome

Abstract

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. We evaluated the effects of a single CNF1 intracerebroventricular inoculation in a mouse model of Rett syndrome (RTT), a rare neurodevelopmental disorder and a genetic cause of mental retardation, for which no effective therapy is available. Fully symptomatic MeCP2-308 male mice were 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 and spectroscopy (MRS) were also applied to assess morphological and metabolic brain changes. 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. A partial rescue of the overexpression of IL-6 cytokine was also observed in RTT brains. 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. These results clearly indicate that modulation of brain RhoGTPases by CNF1 may constitute a totally innovative therapeutic approach for RTT and, possibly, for other disorders associated with mental retardation.

Long-lasting efficacy of the cognitive enhancer Cytotoxic Necrotizing Factor 1

“…In these models, reduced LTP has been reported (Fernandez et al, 2007;Lauterborn et al, 2007;Townsend et al, 2010) along with derangement of Rho signaling (MendozaNaranjo et al, 2007;Petratos et al, 2008) and/or alterations of the dendritic tree/spines (Benavides-Piccione et al, 2004;Comery et al, 1997;Perez-Cruz et al, 2011). Experimental approaches based on Rho modulation have shown pre-clinical efficacy in animal models of ID (Bongmba et al, 2011;De Filippis et al, 2011). CNF1 shows high potency in modulating Rho, Rac and Cdc42, which play pivotal role in dendrite morphogenesis, and here we confirm that the molecule enhances memory and LTP.…”

Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability

“…Small GTPases have a crucial role in cytoskeleton dynamics, Truncating IQSEC2 mutations in severe ID F Tran Mau-Them et al suggesting a common physiological pathway via abnormal small GTPase signalling [11][12][13][14][15][16][17] in patients with severe ID, seizures, postnatal microcephaly and stereotypic midlines movements.…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…For example, ICV injection of CNF1 has been reported to reduce locomotor hyperactivity and to partially correct memory deficits typically seen in the hAPP (Swedish and Indiana mutations) TgCRND8 AD mouse model [45]. CNF1 can also improve the behavioral and astrocytic deficits in a mouse model of Rett syndrome [46]. It should be pointed out that as CNF1 targets all 3 Rho-GTPases (i.e., RhoA, Rac1, and Cdc42) for activation, it is unlikely that it simply corrects a possible imbalance in Rho-GTPase signaling in AD, and the possibility that the beneficial effects could be nonspecific and unrelated to any direct action on AD pathology cannot be ruled out.…”