Letter

Kctd13 deletion reduces synaptic transmission via increased RhoA

Received:
Accepted:
Published online:

Abstract

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.

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Acknowledgements

This research was supported by National Institutes of Health (NIH) R01HD069560 and R01HD069560-S1, Autism Speaks, The Hartwell Foundation, Ed and Sue Rose Distinguished Professorship in Neurology, gifts from C. Heighten, D. Caudy and BRAINS for Autism (to C.M.P.), Autism Science Foundation (to C.M.P. and C.O.E.), Canadian Institute for Health Research and Ontario Brain Institute (to J.P.L.), NIH 2K02DA023555 and NASA NNX15AE09G (to A.J.E.), Uehara Foundation (to N.U.), NIH MH102603 (to G.K.), NIH K99MH110603 (to S.B.T.), Damon Runyon Cancer Research Foundation (to S.B.T.), Harvard Brain Institute Bipolar Seed Grant (to A.F.S.), and NIH R01HL109525 (to A.F.S). We thank K. R. Tolias for RhoA KO mouse brain and the University of Texas Southwestern Whole Brain Microscopy Facility (WBMF) for assistance with X-gal histology and slide scanning. The WBMF is supported by the Texas Institute for Brain Injury and Repair. Embryonic stem cells were generated by the trans-NIH Knockout Mouse Project (KOMP) from the KOMP Repository (www.komp.org). NIH grants to Velocigene at Regeneron (U01HG004085) and the CSD Consortium (U01HG004080) funded generation of gene-targeted embryonic stem cells for 8,500 genes (KOMP), archived and distributed by the KOMP Repository at the University of California, Davis, and CHORI (U42RR024244).

Author information

Author notes

    • Irina Filonova
    • , Noriyoshi Usui
    •  & Amelia J. Eisch

    Present addresses: Faculty Affairs Office, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa, Japan 904-0495 (I.F.); Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui 910-1193, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka 565-0871, Japan (N.U.); Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-4318, USA (A.J.E.); Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318, USA (A.J.E.).

    • Christine Ochoa Escamilla
    •  & Irina Filonova

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA

    • Christine Ochoa Escamilla
    • , Irina Filonova
    • , Angela K. Walker
    • , Zhong X. Xuan
    • , Roopashri Holehonnur
    • , Felipe Espinosa
    • , Shunan Liu
    • , Isabel A. López-García
    • , Dorian B. Mendoza
    • , Haley E. Speed
    •  & Craig M. Powell
  2. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Summer B. Thyme
    •  & Alexander F. Schier
  3. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Noriyoshi Usui
    • , Genevieve Konopka
    •  & Craig M. Powell
  4. Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada

    • Jacob Ellegood
    •  & Jason P. Lerch
  5. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Amelia J. Eisch
    •  & Craig M. Powell
  6. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada

    • Jason P. Lerch
  7. Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA

    • Alexander F. Schier
  8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Alexander F. Schier
  9. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • Alexander F. Schier
  10. FAS Center for Systems Biology, Harvard University, Harvard, Massachusetts 02138, USA

    • Alexander F. Schier

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Contributions

C.O.E., I.F., S.B.T., J.E. and C.M.P. designed the study and wrote the paper. All authors edited and approved the manuscript. Z.X.X. generated, confirmed, and genotyped mice with aid from S.L. C.O.E. performed/analysed data for field and whole-cell electrophysiology, biochemistry, and field electrophysiology with rhosin and C3. F.E. performed/analysed MK-801 whole-cell electrophysiology. H.E.S. performed whole-cell electrophysiology with rhosin, miniature inhibitory postsynaptic currents (mIPSCs), and cortical mEPSCs. C.O.E. analysed the data. I.A.L. contributed to biochemistry. I.F. performed biochemistry, immunohistochemistry, and neurogenesis with supervision by A.J.E. I.F. and A.K.W. performed embryonic neurogenesis and A.K.W. analysed the data with consultation by A.J.E. N.U. performed IUE supervised by G.K., I.F. sectioned and stained tissue, and A.K.W. analysed data. I.F. performed cortical layer staining, and R.H. and D.B.M. analysed data. S.B.T. performed zebrafish studies with supervision by A.F.S. J.E. performed and analysed mouse MRI experiments supervised by J.P.L.

Competing interests

C.M.P. has accepted travel funds/honoraria to speak once at the following companies: Psychogenics; Astra-Zeneca; Roche; Pfizer; and Dainippon Sumitomo Pharma Co. C.M.P. has an investigator-initiated Novartis grant for clinical research. None of these relates to the current study.

Corresponding author

Correspondence to Craig M. Powell.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

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    This file contains supplementary results, supplementary online table 1 – detailed statistics, supplementary online figure S1 – blot source images, and the main text paragraphs with extra references.