Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development.
K. L. Pettem, D. Yokomaku, H. Takahashi, Y. Ge, and A. M. Craig (2013)
J. Cell Biol. 200, 321-336
   Abstract »    Full Text »    PDF »
Polysialylated NCAM and EphrinA/EphA Regulate Synaptic Development of GABAergic Interneurons in Prefrontal Cortex.
L. H. Brennaman, X. Zhang, H. Guan, J. W. Triplett, A. Brown, G. P. Demyanenko, P. B. Manis, L. Landmesser, and P. F. Maness (2013)
Cereb Cortex 23, 162-177
   Abstract »    Full Text »    PDF »
Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice.
T. Sadakata, Y. Shinoda, M. Oka, Y. Sekine, Y. Sato, C. Saruta, H. Miwa, M. Tanaka, S. Itohara, and T. Furuichi (2012)
PNAS 109, 21104-21109
   Abstract »    Full Text »    PDF »
Accumulation of {alpha}-Synuclein Triggered by Presynaptic Dysfunction.
Y. Nakata, T. Yasuda, M. Fukaya, S. Yamamori, M. Itakura, T. Nihira, H. Hayakawa, A. Kawanami, M. Kataoka, M. Nagai, et al. (2012)
J. Neurosci. 32, 17186-17196
   Abstract »    Full Text »    PDF »
Review Article: General Anesthesia: A Gateway to Modulate Synapse Formation and Neural Plasticity?.
L. Vutskits (2012)
Anesth. Analg. 115, 1174-1182
   Abstract »    Full Text »    PDF »
Autism-Associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin-Neuroligin-Mediated Transsynaptic Signaling.
M. H. Arons, C. J. Thynne, A. M. Grabrucker, D. Li, M. Schoen, J. E. Cheyne, T. M. Boeckers, J. M. Montgomery, and C. C. Garner (2012)
J. Neurosci. 32, 14966-14978
   Abstract »    Full Text »    PDF »
Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism.
S. J. Baudouin, J. Gaudias, S. Gerharz, L. Hatstatt, K. Zhou, P. Punnakkal, K. F. Tanaka, W. Spooren, R. Hen, C. I. De Zeeuw, et al. (2012)
Science 338, 128-132
   Abstract »    Full Text »    PDF »
The molecular basis of cognitive deficits in pervasive developmental disorders.
A. Bhattacharya and E. Klann (2012)
Learn. Mem. 19, 434-443
   Abstract »    Full Text »    PDF »
Multiple Roles for Mammalian Target of Rapamycin Signaling in Both Glutamatergic and GABAergic Synaptic Transmission.
M. C. Weston, H. Chen, and J. W. Swann (2012)
J. Neurosci. 32, 11441-11452
   Abstract »    Full Text »    PDF »
Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.
J. Veenstra-VanderWeele, C. L. Muller, H. Iwamoto, J. E. Sauer, W. A. Owens, C. R. Shah, J. Cohen, P. Mannangatti, T. Jessen, B. J. Thompson, et al. (2012)
PNAS 109, 5469-5474
   Abstract »    Full Text »    PDF »
Synaptic Cell Adhesion.
M. Missler, T. C. Sudhof, and T. Biederer (2012)
Cold Spring Harb Perspect Biol 4, a005694
   Abstract »    Full Text »    PDF »
Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities.
H. Y. Zoghbi and M. F. Bear (2012)
Cold Spring Harb Perspect Biol 4, a009886
   Abstract »    Full Text »    PDF »
Increased Gene Dosage of Ube3a Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice.
S. E. P. Smith, Y.-D. Zhou, G. Zhang, Z. Jin, D. C. Stoppel, and M. P. Anderson (2011)
Science Translational Medicine 3, 103ra97
   Abstract »    Full Text »    PDF »
Mouse model of Timothy syndrome recapitulates triad of autistic traits.
P. L. Bader, M. Faizi, L. H. Kim, S. F. Owen, M. R. Tadross, R. W. Alfa, G. C. L. Bett, R. W. Tsien, R. L. Rasmusson, and M. Shamloo (2011)
PNAS 108, 15432-15437
   Abstract »    Full Text »    PDF »
Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function.
M. Etherton, C. Foldy, M. Sharma, K. Tabuchi, X. Liu, M. Shamloo, R. C. Malenka, and T. C. Sudhof (2011)
PNAS 108, 13764-13769
   Abstract »    Full Text »    PDF »
MET signaling in GABAergic neuronal precursors of the medial ganglionic eminence restricts GDNF activity in cells that express GFR{alpha}1 and a new transmembrane receptor partner.
M. Perrinjaquet, D. Sjostrand, A. Moliner, S. Zechel, F. Lamballe, F. Maina, and C. F. Ibanez (2011)
J. Cell Sci. 124, 2797-2805
   Abstract »    Full Text »    PDF »
Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia.
C. Sun, M.-C. Cheng, R. Qin, D.-L. Liao, T.-T. Chen, F.-J. Koong, G. Chen, and C.-H. Chen (2011)
Hum. Mol. Genet. 20, 3042-3051
   Abstract »    Full Text »    PDF »
Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons.
J. Ko, G. J. Soler-Llavina, M. V. Fuccillo, R. C. Malenka, and T. C. Sudhof (2011)
J. Cell Biol. 194, 323-334
   Abstract »    Full Text »    PDF »
Selective impact of MeCP2 and associated histone deacetylases on the dynamics of evoked excitatory neurotransmission.
E. D. Nelson, M. Bal, E. T. Kavalali, and L. M. Monteggia (2011)
J Neurophysiol 106, 193-201
   Abstract »    Full Text »    PDF »
Deletion of the Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Auxiliary Subunit TRIP8b Impairs Hippocampal Ih Localization and Function and Promotes Antidepressant Behavior in Mice.
A. S. Lewis, S. P. Vaidya, C. A. Blaiss, Z. Liu, T. R. Stoub, D. H. Brager, X. Chen, R. A. Bender, C. M. Estep, A. B. Popov, et al. (2011)
J. Neurosci. 31, 7424-7440
   Abstract »    Full Text »    PDF »
Temporally Specified Genetic Ablation of Neurogenesis Impairs Cognitive Recovery after Traumatic Brain Injury.
C. A. Blaiss, T.-S. Yu, G. Zhang, J. Chen, G. Dimchev, L. F. Parada, C. M. Powell, and S. G. Kernie (2011)
J. Neurosci. 31, 4906-4916
   Abstract »    Full Text »    PDF »
Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism.
R. Mejias, A. Adamczyk, V. Anggono, T. Niranjan, G. M. Thomas, K. Sharma, C. Skinner, C. E. Schwartz, R. E. Stevenson, M. D. Fallin, et al. (2011)
PNAS 108, 4920-4925
   Abstract »    Full Text »    PDF »
Pten Knockdown In Vivo Increases Excitatory Drive onto Dentate Granule Cells.
B. W. Luikart, E. Schnell, E. K. Washburn, A. L. Bensen, K. R. Tovar, and G. L. Westbrook (2011)
J. Neurosci. 31, 4345-4354
   Abstract »    Full Text »    PDF »
Differential dynamics and activity-dependent regulation of {alpha}- and {beta}-neurexins at developing GABAergic synapses.
Y. Fu and Z. J. Huang (2010)
PNAS 107, 22699-22704
   Abstract »    Full Text »    PDF »
Behavioral and Cerebellar Transmission Deficits in Mice Lacking the Autism-Linked Gene Islet Brain-2.
J. Giza, M. J. Urbanski, F. Prestori, B. Bandyopadhyay, A. Yam, V. Friedrich, K. Kelley, E. D'Angelo, and M. Goldfarb (2010)
J. Neurosci. 30, 14805-14816
   Abstract »    Full Text »    PDF »
Neuroligin Trafficking Deficiencies Arising from Mutations in the {alpha}/{beta}-Hydrolase Fold Protein Family.
A. De Jaco, M. Z. Lin, N. Dubi, D. Comoletti, M. T. Miller, S. Camp, M. Ellisman, M. T. Butko, R. Y. Tsien, and P. Taylor (2010)
J. Biol. Chem. 285, 28674-28682
   Abstract »    Full Text »    PDF »
The Planar Polarity Protein Scribble1 Is Essential for Neuronal Plasticity and Brain Function.
M. M. Moreau, N. Piguel, T. Papouin, M. Koehl, C. M. Durand, M. E. Rubio, F. Loll, E. M. Richard, C. Mazzocco, C. Racca, et al. (2010)
J. Neurosci. 30, 9738-9752
   Abstract »    Full Text »    PDF »
Defective GABAergic Neurotransmission and Pharmacological Rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome.
J. L. Olmos-Serrano, S. M. Paluszkiewicz, B. S. Martin, W. E. Kaufmann, J. G. Corbin, and M. M. Huntsman (2010)
J. Neurosci. 30, 9929-9938
   Abstract »    Full Text »    PDF »
RIM1{alpha} and Interacting Proteins Involved in Presynaptic Plasticity Mediate Prepulse Inhibition and Additional Behaviors Linked to Schizophrenia.
J. Blundell, P. S. Kaeser, T. C. Sudhof, and C. M. Powell (2010)
J. Neurosci. 30, 5326-5333
   Abstract »    Full Text »    PDF »
SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles.
D. Castermans, K. Volders, A. Crepel, L. Backx, R. De Vos, K. Freson, S. Meulemans, J. R. Vermeesch, C. T.R.M. Schrander-Stumpel, P. De Rijk, et al. (2010)
Hum. Mol. Genet. 19, 1368-1378
   Abstract »    Full Text »    PDF »
Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior.
J. Blundell, C. A. Blaiss, M. R. Etherton, F. Espinosa, K. Tabuchi, C. Walz, M. F. Bolliger, T. C. Sudhof, and C. M. Powell (2010)
J. Neurosci. 30, 2115-2129
   Abstract »    Full Text »    PDF »
Mouse neurexin-1{alpha} deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.
M. R. Etherton, C. A. Blaiss, C. M. Powell, and T. C. Sudhof (2009)
PNAS 106, 17998-18003
   Abstract »    Full Text »    PDF »
A Neuroligin-4 Missense Mutation Associated with Autism Impairs Neuroligin-4 Folding and Endoplasmic Reticulum Export.
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)
J. Neurosci. 29, 10843-10854
   Abstract »    Full Text »    PDF »
Regionalized Loss of Parvalbumin Interneurons in the Cerebral Cortex of Mice with Deficits in GFR{alpha}1 Signaling.
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 »
Neuroligin 2 Controls the Maturation of GABAergic Synapses and Information Processing in the Retina.
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)
Nucleic Acids Res. 37, 1269-1279
   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)
PNAS 105, 20947-20952
   Abstract »    Full Text »    PDF »
Kalirin-7 Is Required for Synaptic Structure and Function.
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 »
Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals.
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)
PNAS 105, 9087-9092
   Abstract »    Full Text »    PDF »
Synaptic Imbalance, Stereotypies, and Impaired Social Interactions in Mice with Altered Neuroligin 2 Expression.
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)
J. Neurosci. 28, 6055-6067
   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 »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882