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 TejidosRESUMEN
Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.
