16p11.2 Autism Risk Gene Kctd13 Deletion Reduces Synaptic Transmission Via Increased RhoA

Oral Presentation
Thursday, May 10, 2018: 2:40 PM
Willem Burger Hal (de Doelen ICC Rotterdam)
C. M. Powell1, C. O. Escamilla2, I. Filonova2,3, A. K. Walker2, Z. X. Xuan2, R. Holehonnur2, F. Espinosa2, S. Liu2, S. B. Thyme4, I. A. Lopez-Garcia2, D. B. Mendoza2, N. Usui2,5,6, J. Ellegood7, A. J. Eisch2,8, G. Konopka2, J. P. Lerch9, A. F. Schier10 and H. Speed2, (1)Neurobiology, UAB School of Medicine, Birmingham, AL, (2)The University of Texas Southwestern Medical Center, Dallas, TX, (3)Okinawa Institute of Science and Technology, Okinawa, Japan, (4)Molecular and Cellular Biology, Harvard University, Cambridge, MA, (5)Division of Developmental Mental Functions, University of Fukui, Fukui, Japan, (6)United Graduate School of Child Development, Osaka University, Osaka, Japan, (7)Hospital for Sick Children, Toronto, ON, Canada, (8)Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, TX, (9)Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada, (10)Harvard University, Cambridge, MA
Background: 16p11.2 deletions and duplications are genetic risk factors for multiple neuropsychiatric conditions including autism, intellectual disability, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, bipolar, epilepsy, and obesity as well as alterations in brain size and head circumference. This chromosomal region contains ~29 genes, none of which has been individually linked to 16p11.2-associated neuropsychiatric disorders. Additional human genetic findings, however, do suggest a smaller critical region of 5 genes or less that includes the potassium-channel-tetramerization-domain-containing 13 gene (KCTD13, a.k.a. BACURD1, POLDIP1, PDIP1, TNFAIP1-like). Kctd13 has been implicated in brain size in 16p11.2 CNVs via morpholino-mediated knockdown of Kctd13 in zebrafish. 16p11.2 copy number variants (CNV) are among the most prevalent CNVs in autism spectrum disorders (ASDs). Of many 16p11.2 genes, KCTD13 has been implicated as a major driver of neurodevelopmental phenotypes. The function of KCTD13 in mammalian brain, however, remains unknown. Because KCTD13 is known to regulate levels of the small GTPase RhoA in HeLa cells in culture and because RhoA regulates actin dynamics, we hypothesized that KCTD13 modulates synaptic transmission in the brain.

Objectives: To determine the role of Kctd13 in mammalian brain using a novel genetic mouse model lacking the Kctd13 gene.

Methods: We characterize our novel Kctd13 deletion mouse model using protein biochemistry, acute hippocampus slice electrophysiology whole-cell and extracellular recordings, neuronal morphological analysis, molecular biology tools, and behavior along with in vitro pharmacology.

Results: Here we delete Kctd13 in mice and demonstrate reduced synaptic transmission in the hippocampus. Reduced synaptic transmission correlates with increased levels of RhoA, a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition with two distinct inhibitors, suggesting increased RhoA as an important mechanism. Similar effects on synaptic transmission were observed at cortical synapses. In contrast to a previous knockdown study, deletion of Kctd13 does not increase brain size or neurogenesis in mice or zebrafish.

Conclusions: These findings implicate Kctd13 in 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.