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J. Biol. Chem., Vol. 280, Issue 23, 22365-22374, June 10, 2005

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Dissection of Synapse Induction by Neuroligins

EFFECT OF A NEUROLIGIN MUTATION ASSOCIATED WITH AUTISM^*

Alexander A. Chubykin, Xinran Liu, Davide Comoletti¶, Igor Tsigelny¶, Palmer Taylor¶, and Thomas C. Südhof||**

From the Center for Basic Neuroscience, Department of Molecular Genetics, and ^||Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9111, and ^¶Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636

To study synapse formation by neuroligins, we co-cultured hippocampal neurons with COS cells expressing wild type and mutant neuroligins. The large size of COS cells makes it possible to test the effect of neuroligins presented over an extended surface area. We found that a uniform lawn of wild type neuroligins displayed on the cell surface triggers the formation of hundreds of uniformly sized, individual synaptic contacts that are labeled with neurexin antibodies. Electron microscopy revealed that these artificial synapses contain a presynaptic active zone with docked vesicles and often feature a postsynaptic density. Neuroligins 1, 2, and 3 were active in this assay. Mutations in two surface loops of neuroligin 1 abolished neuroligin binding to neurexin 1, a presumptive presynaptic binding partner for postsynaptic neuroligins, and blocked synapse formation. An analysis of mutant neuroligins with an amino acid substitution that corresponds to a mutation described in patients with an autistic syndrome confirmed previous reports that these mutant neuroligins have a compromised capacity to be transported to the cell surface. Nevertheless, the small percentage of mutant neuroligins that reached the cell surface still induced synapse formation. Viewed together, our data suggest that neuroligins generally promote artificial synapse formation in a manner that is associated with -neurexin binding and results in morphologically well differentiated synapses and that a neuroligin mutation found in autism spectrum disorders impairs cell-surface transport but does not completely abolish synapse formation activity.

Received for publication, September 17, 2004 , and in revised form, February 10, 2005.

^* This work was supported by grants from the National Institute of Mental Health (R37 MH52804-08) (to T. C. S.), the National Institutes of Health (R37 GM18360-29) (to P. T.), and the National alliance for autism Research Grant 843 (to D. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: University of Texas Southwestern Medical Center, NA4.118, 6000 Harry Hines Blvd., Dallas, TX 75390-9111. Tel.: 214-648-1876; Fax: 214-648-1879; E-mail: Thomas.Sudhof{at}UTSouthwestern.edu.

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