RESUMEN
Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders and are among the most prevalent in autism spectrum disorders. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
Asunto(s)
Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Eliminación de Gen , Transmisión Sináptica/genética , Proteínas de Pez Cebra/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/psicología , Trastorno Autístico/genética , Trastorno Autístico/psicología , Encéfalo/anatomía & histología , Encéfalo/citología , Encéfalo/patología , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/patología , Proteínas Portadoras/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/psicología , Cromosomas Humanos Par 16/genética , Proteínas Cullin/metabolismo , Femenino , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Masculino , Ratones , Herencia Multifactorial/genética , Neurogénesis/genética , Tamaño de los Órganos/genética , Reproducibilidad de los Resultados , Transmisión Sináptica/efectos de los fármacos , Complejos de Ubiquitina-Proteína Ligasa , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Unión al GTP rho/antagonistas & inhibidores , Proteína de Unión al GTP rhoARESUMEN
Autism Spectrum Disorder (ASD) is a developmental disorder in which children display repetitive behavior, restricted range of interests, and atypical social interaction and communication. CUL3, coding for a Cullin family scaffold protein mediating assembly of ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors, has been identified as a high-risk gene for autism. Although complete knockout of Cul3 results in embryonic lethality, Cul3 heterozygous mice have reduced CUL3 protein, demonstrate comparable body weight, and display minimal behavioral differences including decreased spatial object recognition memory. In measures of reciprocal social interaction, Cul3 heterozygous mice behaved similarly to their wild-type littermates. In area CA1 of hippocampus, reduction of Cul3 significantly increased mEPSC frequency but not amplitude nor baseline evoked synaptic transmission or paired-pulse ratio. Sholl and spine analysis data suggest there is a small yet significant difference in CA1 pyramidal neuron dendritic branching and stubby spine density. Unbiased proteomic analysis of Cul3 heterozygous brain tissue revealed dysregulation of various cytoskeletal organization proteins, among others. Overall, our results suggest that Cul3 heterozygous deletion impairs spatial object recognition memory, alters cytoskeletal organization proteins, but does not cause major hippocampal neuronal morphology, functional, or behavioral abnormalities in adult global Cul3 heterozygous mice.