Long-lasting efficacy of the cognitive enhancer cytotoxic necrotizing factor 1.
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'.
Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy.
Sonia
S
Borrelli
Marco
M
Musilli
Assunta
A
Martino
Giovanni
G
Diana
D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007858:Learning / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D058573:Performance-Enhancing Substances / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D011897:Random Allocation; D021641:Recognition, Psychology / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D013045:Species Specificity; D009435:Synaptic Transmission / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D058573:Performance-Enhancing Substances; D011994:Recombinant Proteins; C060296:cytotoxic necrotizing factor type 1; D020741:rho GTP-Binding Proteins