Asunto(s)
Quimiocina CXCL12/biosíntesis , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Compuestos Heterocíclicos/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Receptores CXCR4/antagonistas & inhibidores , Animales , Bencilaminas , Ciclamas , Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/administración & dosificación , RatonesRESUMEN
Alterations in dendritic spine numbers are linked to deficits in learning and memory. While we previously revealed that postsynaptic plasticity-related gene 1 (PRG-1) controls lysophosphatidic acid (LPA) signaling at glutamatergic synapses via presynaptic LPA receptors, we now show that PRG-1 also affects spine density and synaptic plasticity in a cell-autonomous fashion via protein phosphatase 2A (PP2A)/ß1-integrin activation. PRG-1 deficiency reduces spine numbers and ß1-integrin activation, alters long-term potentiation (LTP), and impairs spatial memory. The intracellular PRG-1 C terminus interacts in an LPA-dependent fashion with PP2A, thus modulating its phosphatase activity at the postsynaptic density. This results in recruitment of adhesome components src, paxillin, and talin to lipid rafts and ultimately in activation of ß1-integrins. Consistent with these findings, activation of PP2A with FTY720 rescues defects in spine density and LTP of PRG-1-deficient animals. These results disclose a mechanism by which bioactive lipid signaling via PRG-1 could affect synaptic plasticity and memory formation.
Asunto(s)
Espinas Dendríticas/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Integrina beta1/metabolismo , Lisofosfolípidos/metabolismo , Plasticidad Neuronal/fisiología , Proteína Fosfatasa 2/metabolismo , Sinapsis/fisiología , Animales , Células Cultivadas , Espinas Dendríticas/genética , Adhesiones Focales/fisiología , Factores de Intercambio de Guanina Nucleótido/genética , Hipocampo/citología , Hipocampo/metabolismo , Integrina beta1/genética , Potenciación a Largo Plazo , Microdominios de Membrana/metabolismo , Ratones , Ratones Noqueados , Proteína Fosfatasa 2/genética , Factores de Intercambio de Guanina Nucleótido Rho , Transducción de SeñalRESUMEN
During development, axonal projections have a remarkable ability to innervate correct dendritic subcompartments of their target neurons and to form regular neuronal circuits. Altered axonal targeting with formation of synapses on inappropriate neurons may result in neurodevelopmental sequelae, leading to psychiatric disorders. Here we show that altering the expression level of the polysialic acid moiety, which is a developmentally regulated, posttranslational modification of the neural cell adhesion molecule NCAM, critically affects correct circuit formation. Using a chemically modified sialic acid precursor (N-propyl-D: -mannosamine), we inhibited the polysialyltransferase ST8SiaII, the principal enzyme involved in polysialylation during development, at selected developmental time-points. This treatment altered NCAM polysialylation while NCAM expression was not affected. Altered polysialylation resulted in an aberrant mossy fiber projection that formed glutamatergic terminals on pyramidal neurons of the CA1 region in organotypic slice cultures and in vivo. Electrophysiological recordings revealed that the ectopic terminals on CA1 pyramids were functional and displayed characteristics of mossy fiber synapses. Moreover, ultrastructural examination indicated a "mossy fiber synapse"-like morphology. We thus conclude that homeostatic regulation of the amount of synthesized polysialic acid at specific developmental stages is essential for correct synaptic targeting and circuit formation during hippocampal development.
