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J. Biol. Chem., Vol. 280, Issue 17, 17312-17319, April 29, 2005

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Neuroligins Mediate Excitatory and Inhibitory Synapse Formation

INVOLVEMENT OF PSD-95 AND NEUREXIN-1 IN NEUROLIGIN-INDUCED SYNAPTIC SPECIFICITY^*

Joshua N. Levinson, Nadège Chéry¶||, Kun Huang**, Tak Pan Wong¶, Kimberly Gerrow, Rujun Kang, Oliver Prange, Yu Tian Wang¶¶¶, and Alaa El-Husseini||||

From the Departments of Psychiatry and ^¶Medicine, the Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

The balance between excitatory and inhibitory synapses is a tightly regulated process that requires differential recruitment of proteins that dictate the specificity of newly formed contacts. However, factors that control this process remain unidentified. Here we show that members of the neuroligin (NLG) family, including NLG1, NLG2, and NLG3, drive the formation of both excitatory and inhibitory presynaptic contacts. The enrichment of endogenous NLG1 at excitatory contacts and NLG2 at inhibitory synapses supports an important in vivo role for these proteins in the development of both types of contacts. Immunocytochemical and electrophysiological analysis showed that the effects on excitatory and inhibitory synapses can be blocked by treatment with a fusion protein containing the extracellular domain of neurexin-1. We also found that overexpression of PSD-95, a postsynaptic binding partner of NLGs, resulted in a shift in the distribution of NLG2 from inhibitory to excitatory synapses. These findings reveal a critical role for NLGs and their synaptic partners in controlling the number of inhibitory and excitatory synapses. Furthermore, relative levels of PSD-95 alter the ratio of excitatory to inhibitory synaptic contacts by sequestering members of the NLG family to excitatory synapses.

Received for publication, December 8, 2004 , and in revised form, February 7, 2005.

^* This work was supported in part by grants from the Canadian Institutes for Health Research, the Michael Smith Foundation for Health Research, Neuroscience Canada, and EJLB. 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.

The on-line version of this article (available at http://www.jbc.org) contains Suppemental Figs. 1–4.

Supported by Michael Smith Foundation for Health Research and Canadian Institutes for Health Research student fellowships.

^|| Supported by a Fragile X Research Foundation of Canada postdoctoral fellowship.

^** Supported by the Canadian Institutes for Health Research training program.

Supported by a Michael Smith Foundation for Health Research student fellowship.

Supported by a postdoctoral fellowship from the Bluma-Tischler Foundation.

^¶¶ Canadian Institutes for Health Research Investigator and a Howard Hughes Medical Institute International Research Scholar.

^|||| Canadian Institutes for Health Research New Investigator and an Michael Smith Foundation for Health Research Scholar. To whom correspondence should be addressed. E-mail: alaa{at}interchange.ubc.ca.

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