title: CNF1 improves astrocytic ability to support neuronal growth and differentiation in vitro.
abstract: Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number. CNF1 removal, however, restored dendritic tree development and synapse formation, suggesting that the toxin can reversibly block neuronal differentiation. On differentiated neurons, CNF1 had a similar effacing effect on synapses. Therefore, a direct interaction with CNF1 is apparently deleterious for neurons. Since astrocytes play a pivotal role in neuronal differentiation and synaptic regulation, we wondered if the beneficial in vivo effect could be mediated by astrocytes. Primary astrocytes from embryonic cortex were treated with CNF1 for 48 hours and used as a substrate for growing hippocampal neurons. Such neurons showed an increased development of neurites, in respect to age-matched controls, with a wider dendritic tree and a richer content in synapses. In CNF1-exposed astrocytes, the production of interleukin 1β, known to reduce dendrite development and complexity in neuronal cultures, was decreased. These results demonstrate that astrocytes, under the influence of CNF1, increase their supporting activity on neuronal growth and differentiation, possibly related to the diminished levels of interleukin 1β. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy. fiorella.malchiodi@iss.it
authors.forename: Fiorella
authors.initials: F
authors.lastname: Malchiodi-Albedi
authors.forename: Silvia
authors.initials: S
authors.lastname: Paradisi
authors.forename: Michela
authors.initials: M
authors.lastname: Di Nottia
authors.forename: Daiana
authors.initials: D
authors.lastname: Simone
authors.forename: Sara
authors.initials: S
authors.lastname: Travaglione
authors.forename: Loredana
authors.initials: L
authors.lastname: Falzano
authors.forename: Marco
authors.initials: M
authors.lastname: Guidotti
authors.forename: Claudio
authors.initials: C
authors.lastname: Frank
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cutarelli
authors.forename: Alessia
authors.initials: A
authors.lastname: Fabbri
authors.forename: Carla
authors.initials: C
authors.lastname: Fiorentini
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects; D029968:Escherichia coli Proteins / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D053583:Interleukin-1beta; C060296:cytotoxic necrotizing factor type 1; D020741:rho GTP-Binding Proteins