Enhancement of learning and memory after activation of cerebral Rho GTPases.
The mechanism whereby the morphology and connectivity of the dendritic tree is regulated depends on an actin dynamics that, in turn, is controlled by Rho GTPases, a family of small GTP-binding proteins encompassing Rho, Rac, and Cdc42 subfamilies. Cytotoxic necrotizing factor 1 (CNF1), a protein toxin from Escherichia coli, constitutively activates Rho GTPases, thus leading to remodeling of the actin cytoskeleton in intact cells. Here, we show that the modulation of cerebral RhoA and Rac1 activity induced by CNF1 in mice leads to (i) rearrangement of cerebral actin cytoskeleton, (ii) enhanced neurotransmission and synaptic plasticity, and (iii) improved learning and memory in various behavioral tasks. The effects persist for weeks and are not observed in mice treated with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine to cysteine at position 866. The results suggest that learning ability can be improved through pharmacological manipulation of neural connectivity.
Diana
Giovanni
G
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. giovanni.diana@iss.it
Valentini
Giovanni
G
Travaglione
Sara
S
Falzano
Loredana
L
Pieri
Massimo
M
Zona
Cristina
C
Meschini
Stefania
S
Fabbri
Alessia
A
Fiorentini
Carla
C
D000199:Actins / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003603:Cytotoxins / Q000633:toxicity; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004789:Enzyme Activation; D029968:Escherichia coli Proteins / Q000633:toxicity; D005239:Fear / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D000199:Actins; D001427:Bacterial Toxins; D003603:Cytotoxins; D029968:Escherichia coli Proteins; C060296:cytotoxic necrotizing factor type 1; D020741:rho GTP-Binding Proteins