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1.
PLoS One ; 7(4): e34115, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22523545

RESUMEN

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 1ß, 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 1ß. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes.


Asunto(s)
Astrocitos/fisiología , Toxinas Bacterianas/farmacología , Diferenciación Celular/efectos de los fármacos , Proteínas de Escherichia coli/farmacología , Neurogénesis/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/efectos de los fármacos , Interleucina-1beta/biosíntesis , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Ratas Wistar , Sinapsis/efectos de los fármacos , Proteínas de Unión al GTP rho/antagonistas & inhibidores , Proteínas de Unión al GTP rho/metabolismo
2.
Neuropsychopharmacology ; 37(5): 1152-63, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22157810

RESUMEN

RhoGTPases are crucial molecules in neuronal plasticity and cognition, as confirmed by their role in non-syndromic mental retardation. Activation of brain RhoGTPases by the bacterial cytotoxic necrotizing factor 1 (CNF1) reshapes the actin cytoskeleton and enhances neurotransmission and synaptic plasticity in mouse brains. We evaluated the effects of a single CNF1 intracerebroventricular inoculation in a mouse model of Rett syndrome (RTT), a rare neurodevelopmental disorder and a genetic cause of mental retardation, for which no effective therapy is available. Fully symptomatic MeCP2-308 male mice were evaluated in a battery of tests specifically tailored to detect RTT-related impairments. At the end of behavioral testing, brain sections were immunohistochemically characterized. Magnetic resonance imaging and spectroscopy (MRS) were also applied to assess morphological and metabolic brain changes. The CNF1 administration markedly improved the behavioral phenotype of MeCP2-308 mice. CNF1 also dramatically reversed the evident signs of atrophy in astrocytes of mutant mice and restored wt-like levels of this cell population. A partial rescue of the overexpression of IL-6 cytokine was also observed in RTT brains. CNF1-induced brain metabolic changes detected by MRS analysis involved markers of glial integrity and bioenergetics, and point to improved mitochondria functionality in CNF1-treated mice. These results clearly indicate that modulation of brain RhoGTPases by CNF1 may constitute a totally innovative therapeutic approach for RTT and, possibly, for other disorders associated with mental retardation.


Asunto(s)
Astrocitos/fisiología , Síndrome de Rett/enzimología , Síndrome de Rett/patología , Proteínas de Unión al GTP rho/metabolismo , Análisis de Varianza , Animales , Astrocitos/efectos de los fármacos , Toxinas Bacterianas/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Condicionamiento Psicológico/efectos de los fármacos , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Proteínas de Escherichia coli/uso terapéutico , Conducta Exploratoria/efectos de los fármacos , Miedo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Inyecciones Intraventriculares , Interleucina-6/metabolismo , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Destreza Motora/efectos de los fármacos , Destreza Motora/fisiología , Fenotipo , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/genética
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