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ABSTRACT: Small GTPases of the Rho family, including Rho, Rac and CDC42 subfamilies, play key role in neural connectivity and cognition. The pharmacological modulation of these regulatory proteins is associated with enhancement of learning and memory. We sought to determine whether the modulation of cerebral Rho GTPases may correct behavioral disturbances in a mouse model of Alzheimer's disease (AD). TgCRND8 mice show early-onset Abeta amyloid deposits associated with deficits in several cognitive tasks. We report that four-month old TgCRND8 mice display (a) increased locomotor activity in an open field, (b) mild deficits in the learning of a fixed platform position in a water maze task. More markedly, after displacement of the escape platform, TgCRND8 mice exhibit impairment in the learning of the novel position (reversal learning), as they perseverate searching in the familiar position. The administration of the Rho GTPase activator Cytotoxic Necrotizing Factor 1 (CNF1, 1.0fmolkg(-1) intracerebroventricularly) reduces locomotor hyperactivity and corrects the deficits in reversal learning, thus re-establishing normal behavioral plasticity. We conclude that the pharmacological modulation of Rho GTPase signaling might be beneficial for the treatment of AD. Reversal learning in TgCRND8 mice may represent a convenient pre-clinical assay for the efficacy of therapeutic interventions in AD.
Behavioural brain research 09/2012; 237C:223-229. · 3.22 Impact Factor
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ABSTRACT: Rho GTPases are key regulators of the activity-dependent changes of neural circuits. Besides being involved in nervous system development and repair, this neural structural plasticity is believed to constitute the cellular basis of learning and memory. Here we report that concurrent modulation of cerebral Rho GTPases, including Rac, Rho and Cdc42 subfamilies, by Cytotoxic Necrotizing Factor 1 (CNF1, 10 fmol/kg intracerebroventricularly) improves object recognition in both C57BL/6J and CD1 mice. The improvement is long lasting, as it is still observed 90 days post treatment. At this time, the treatment is associated with enhancement of neurotransmission and long-term potentiation. The effects depend on changes in Rho GTPase status, since the recombinant molecule CNF1 C866S, in which the enzymatic activity was abolished through substitution of serine to cysteine at position 866, is ineffective. The study confirms the role of Rho GTPases in learning and suggests that a single administration of CNF1 is effective for a long time after administration. In general, the long-lasting cognition enhancing effect of CNF1 might be beneficial for the treatment of CNS disorders. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
Neuropharmacology 05/2012; 64(1):74-80. · 4.81 Impact Factor
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ABSTRACT: Cerebral Rho GTPases are crucially involved in cognitive abilities. This activity is thought to be related to the regulation of actin polymerization and, thereby, of the shape of the dendritic tree. Here we report that Cytotoxic Necrotizing Factor 1 (CNF1, 1fmol/kgicv), a bacterial protein endowed with Rho GTPase activating properties, enhances working memory for object location/discrimination in C57BL/6 mice. CNF1 selectively increased the exploration of a specific familiar object moved to a position that had been previously occupied by another familiar object. Conversely, the treatment left unaffected (i) exploration of a familiar object moved to a location that was previously unoccupied and (ii) exploration of a novel object. The effects were associated with changes in Rho GTPase status, since CNF1 C866S, a recombinant CNF1 in which the enzymatic activity was abolished through substitution of serine to cysteine at position 866, was ineffective in all the experiments. The study suggests that working memory for specific object-location associations critically depends on neural connectivity. It also confirms the therapeutic potential of the manipulation of Rho GTPase signaling in the modulation of memory processes.
Behavioural brain research 03/2010; 212(1):78-83. · 3.22 Impact Factor
