Kctd13 deletion reduces synaptic transmission via increased RhoA

Experimental evidence that global Kctd13 reduction leads to increased RhoA levels that reduce synaptic transmission, implicating RhoA as a potential therapeutic target for neuropsychiatric disorders associated with copy-number variants that include KCTD13. The 16p11.2 copy-number variant, generated by the deletion of a small piece of chromosome 16, is linked to multiple neuropsychiatric disorders, including autism. A previous study suggested that a gene within this locus, kctd13, could be responsible for neuroanatomical abnormalities in zebrafish. Craig Powell and colleagues fail to replicate neurodevelopmental abnormalities in zebrafish or mice lacking kctd13 or Kctd13, respectively. Rather, they observe reduced synaptic transmission, which correlates with increased levels of RhoA, a KCTD13/CUL3 ubiquitin ligase substrate. Mice lacking Kctd13 did not show many behavioural phenotypes that are signs of autism, such as social deficits or repetitive grooming. These findings do not support a model in which kctd13 or Kctd13 loss alone is responsible for autism-related behaviours, leaving open the possibility of a polygenic mechanism in 16p11.2 deletion syndrome. Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders1,2,3,4,5,6 and are among the most prevalent in autism spectrum disorders1,2,7. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes8,9. 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 study8, 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.