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J. Biol. Chem., Vol. 283, Issue 4, 2323-2334, January 25, 2008

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Induction of GABAergic Postsynaptic Differentiation by -Neurexins^*

Yunhee Kang¹, XueZhao Zhang¹, Frederick Dobie, Huaiyang Wu, and Ann Marie Craig²

From the Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada and the Department of Anatomy and Neurobiology, Washington University, St. Louis, Missouri 63110

β-Neurexin and neuroligin cell adhesion molecules contribute to synapse development in the brain. The longer -neurexins function at both glutamate and -aminobutyric acid (GABA) synapses in coupling to presynaptic calcium channels. Binding of -neurexins to neuroligins was recently reported, but the role of the -neurexins in synapse development has not been well studied. Here we report that in COS cell neuron coculture assays, all three -neurexins induce clustering of the GABAergic postsynaptic scaffolding protein gephyrin and neuroligin 2 but not of the glutamatergic postsynaptic scaffolding protein PSD-95 or neuroligin 1/3/4. -Neurexins also induce clustering of the GABA_A receptor 2 subunit. This synapse promoting activity of -neurexins is mediated by the sixth LNS (laminin neurexin sex hormone-binding protein) domain and negatively modulated by upstream sequences. Although inserts at splice site 4 (S4) in β-neurexins promote greater clustering activity for GABA than glutamate proteins in coculture assay, -neurexin-specific sequences confer complete specificity for GABA proteins. We further report a developmental increase in the ratio of -S4 to +S4 forms of neurexins correlating with an increase in glutamate relative to GABA synaptogenesis and activity regulation of splicing at S4. Thus, +S4 β-neurexins and, even more selectively, -neurexins may be mediators of GABAergic synaptic protein recruitment and stabilization.

Received for publication, May 14, 2007 , and in revised form, October 3, 2007.

^* This work was supported by National Institutes of Health Grant R01 MH-070860 and grants from the Canada Research Chair, Canadian Institutes of Health Research (CIHR) and Michael Smith Foundation for Health Research (MSFHR) (to A. M. C.) and fellowships from CIHR and MSFHR (to F. D.). 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 supplemental Figs. S1-S4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Brain Research Centre, Rm. F149, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. Tel.: 604-822-7283; Fax: 604-822-7299; E-mail: amcraig{at}interchange.ubc.ca.

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