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Science 318 (5847): 71-76

Copyright © 2007 by the American Association for the Advancement of Science

A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice

Katsuhiko Tabuchi,1 Jacqueline Blundell,2 Mark R. Etherton,1 Robert E. Hammer,3 Xinran Liu,1 Craig M. Powell,24 Thomas C. Südhof156*

Abstract: Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell-adhesion molecules. We introduced one of these mutations into mice: the Arg451->Cys451 (R451C) substitution in neuroligin-3. R451C mutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C knockin mice may be a useful model for studying autism-related behaviors.

1 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4 Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

* To whom correspondence should be addressed. E-mail: thomas.sudhof{at}utsouthwestern.edu


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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C. Zhang, J. M. Milunsky, S. Newton, J. Ko, G. Zhao, T. A. Maher, H. Tager-Flusberg, M. F. Bolliger, A. S. Carter, A. A. Boucard, et al. (2009)
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   Abstract »    Full Text »    PDF »
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A. J. Canty, J. Dietze, M. Harvey, H. Enomoto, J. Milbrandt, and C. F. Ibanez (2009)
J. Neurosci. 29, 10695-10705
   Abstract »    Full Text »    PDF »
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M. Hoon, G. Bauer, J.-M. Fritschy, T. Moser, B. H. Falkenburger, and F. Varoqueaux (2009)
J. Neurosci. 29, 8039-8050
   Abstract »    Full Text »    PDF »
FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure.
M. Bensaid, M. Melko, E. G. Bechara, L. Davidovic, A. Berretta, M. V. Catania, J. Gecz, E. Lalli, and B. Bardoni (2009)
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   Abstract »    Full Text »    PDF »
Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist.
C Lintas and A M Persico (2009)
J. Med. Genet. 46, 1-8
   Abstract »    Full Text »    PDF »
Activity-independent and subunit-specific recruitment of functional AMPA receptors at neurexin/neuroligin contacts.
M. Heine, O. Thoumine, M. Mondin, B. Tessier, G. Giannone, and D. Choquet (2008)
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   Abstract »    Full Text »    PDF »
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X.-M. Ma, D. D. Kiraly, E. D. Gaier, Y. Wang, E.-J. Kim, E. S. Levine, B. A. Eipper, and R. E. Mains (2008)
J. Neurosci. 28, 12368-12382
   Abstract »    Full Text »    PDF »
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J. Kim, S.-Y. Jung, Y. K. Lee, S. Park, J.-S. Choi, C. J. Lee, H.-S. Kim, Y.-B. Choi, P. Scheiffele, C. H. Bailey, et al. (2008)
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   Abstract »    Full Text »    PDF »
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R. M. Hines, L. Wu, D. J. Hines, H. Steenland, S. Mansour, R. Dahlhaus, R. R. Singaraja, X. Cao, E. Sammler, S. G. Hormuzdi, et al. (2008)
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   Abstract »    Full Text »    PDF »
A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition.
M. Kvajo, H. McKellar, P. A. Arguello, L. J. Drew, H. Moore, A. B. MacDermott, M. Karayiorgou, and J. A. Gogos (2008)
PNAS 105, 7076-7081
   Abstract »    Full Text »    PDF »
Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells.
E. Fujita, Y. Tanabe, A. Shiota, M. Ueda, K. Suwa, M. Y. Momoi, and T. Momoi (2008)
PNAS 105, 3117-3122
   Abstract »    Full Text »    PDF »
Smaller Dendritic Spines, Weaker Synaptic Transmission, but Enhanced Spatial Learning in Mice Lacking Shank1.
A. Y. Hung, K. Futai, C. Sala, J. G. Valtschanoff, J. Ryu, M. A. Woodworth, F. L. Kidd, C. C. Sung, T. Miyakawa, M. F. Bear, et al. (2008)
J. Neurosci. 28, 1697-1708
   Abstract »    Full Text »    PDF »
Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2.
J. Koehnke, X. Jin, E. C. Budreck, S. Posy, P. Scheiffele, B. Honig, and L. Shapiro (2008)
PNAS 105, 1873-1878
   Abstract »    Full Text »    PDF »
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.
S. Jamain, K. Radyushkin, K. Hammerschmidt, S. Granon, S. Boretius, F. Varoqueaux, N. Ramanantsoa, J. Gallego, A. Ronnenberg, D. Winter, et al. (2008)
PNAS 105, 1710-1715
   Abstract »    Full Text »    PDF »
Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia.
G. Kirov, D. Gumus, W. Chen, N. Norton, L. Georgieva, M. Sari, M. C O'Donovan, F. Erdogan, M. J Owen, H.-H. Ropers, et al. (2008)
Hum. Mol. Genet. 17, 458-465
   Abstract »    Full Text »    PDF »
Testing Hypotheses About Autism.
J. N. Crawley (2007)
Science 318, 56-57
   Abstract »    Full Text »    PDF »

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