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A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice
Katsuhiko Tabuchi,1Jacqueline Blundell,2Mark R. Etherton,1Robert E. Hammer,3Xinran Liu,1Craig M. Powell,2,4Thomas C. Südhof1,5,6*
Autism spectrum disorders (ASDs) are characterized by impairmentsin social behaviors that are sometimes coupled to specializedcognitive abilities. A small percentage of ASD patients carrymutations in genes encoding neuroligins, which are postsynapticcell-adhesion molecules. We introduced one of these mutationsinto mice: the Arg451Cys451 (R451C) substitution in neuroligin-3.R451C mutant mice showed impaired social interactions but enhancedspatial learning abilities. Unexpectedly, these behavioral changeswere accompanied by an increase in inhibitory synaptic transmissionwith no apparent effect on excitatory synapses. Deletion ofneuroligin-3, in contrast, did not cause such changes, indicatingthat the R451C substitution represents a gain-of-function mutation.These data suggest that increased inhibitory synaptic transmissionmay contribute to human ASDs and that the R451C knockin micemay 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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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. 
