title: Behavioral effects of Rho GTPase modulation in a model of Alzheimer's disease.
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, 1.0 fmol kg(-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.
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Musilli
authors.forename: Vincenzina
authors.initials: V
authors.lastname: Nicolia
authors.forename: Sonia
authors.initials: S
authors.lastname: Borrelli
authors.forename: Sigfrido
authors.initials: S
authors.lastname: Scarpa
authors.forename: Giovanni
authors.initials: G
authors.lastname: Diana
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001427:Bacterial Toxins / Q000627:therapeutic use; D004195:Disease Models, Animal; D020536:Enzyme Activators / Q000627:therapeutic use*; D029968:Escherichia coli Proteins / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007859:Learning Disabilities / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D045442:Rotarod Performance Test; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D001427:Bacterial Toxins; D020536:Enzyme Activators; D029968:Escherichia coli Proteins; C060296:cytotoxic necrotizing factor type 1; D020741:rho GTP-Binding Proteins