RESUMEN

The molecular mechanisms that promote excitatory synapse development have been extensively studied. However, the molecular events preventing precocious excitatory synapse development so that synapses form at the correct time and place are less well understood. Here, we report the functional characterization of ARHGAP12, a previously uncharacterized Rho GTPase-activating protein (RhoGAP) in the brain. ARHGAP12 is specifically expressed in the CA1 region of the hippocampus, where it localizes to the postsynaptic compartment of excitatory synapses. ARHGAP12 negatively controls spine size via its RhoGAP activity and promotes, by interacting with CIP4, postsynaptic AMPA receptor endocytosis. Arhgap12 knockdown results in precocious maturation of excitatory synapses, as indicated by a reduction in the proportion of silent synapses. Collectively, our data show that ARHGAP12 is a synaptic RhoGAP that regulates excitatory synaptic structure and function during development.

Asunto(s)

Proteínas Activadoras de GTPasa/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas Asociadas a Microtúbulos/genética , Antígenos de Histocompatibilidad Menor/genética , Células Piramidales/metabolismo , Receptores AMPA/genética , Sinapsis/fisiología , Animales , Animales Recién Nacidos , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/metabolismo , Espinas Dendríticas/fisiología , Espinas Dendríticas/ultraestructura , Embrión de Mamíferos , Endocitosis , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Técnicas de Placa-Clamp , Cultivo Primario de Células , Células Piramidales/citología , Ratas , Ratas Wistar , Receptores AMPA/metabolismo , Análisis de la Célula Individual , Sinapsis/ultraestructura , Transmisión Sináptica , Técnicas de Cultivo de Tejidos