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The Journal of Neuroscience, April 19, 2006, 26(16):4256-4265; doi:10.1523/JNEUROSCI.1253-05.2006

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Cellular/Molecular
Structure Function and Splice Site Analysis of the Synaptogenic Activity of the Neurexin-1 LNS Domain

Ethan R. Graf,¹ Yunhee Kang,^1,2,3 Anna M. Hauner,¹ and Ann Marie Craig^1,2

¹Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, ²Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5, and ³Department of Anatomy and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul, South Korea

Correspondence should be addressed to Ann Marie Craig, Brain Research Centre, University of British Columbia Hospital F149, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Email: amcraig{at}interchange.ubc.ca

Recent findings suggest that the neurexin-neuroligin link promotes both GABAergic and glutamatergic synaptogenesis, but the mechanism by which neurexins influence the clustering of appropriate neuroligins and postsynaptic differentiation remains unclear. Previous studies suggested that the presence or absence of alternatively spliced residues at splice site 4 (S4) in the neurexin LNS domain may regulate neurexin function. We demonstrate that addition of the S4 insert selectively reduces the ability of neurexin-1 to cluster neuroligin-1/3/4 and glutamatergic postsynaptic proteins, although clustering of neuroligin-2 and GABAergic postsynaptic proteins remain strong. Furthermore, addition of the S4 insert decreases the binding affinity of neurexin-1 to neuroligins-1 and -4 but has little effect on binding to neuroligins-2 and -3. Additional structure-function studies reveal the neurexin binding interface mediating synaptogenic activity to be composed primarily of residues in the 23, 67, and 1011 loops on one rim of the LNS domain sandwich. Mutation of two predicted Ca²⁺-binding residues disrupts postsynaptic protein clustering and binding to neuroligins, consistent with previous findings that neurexin-neuroligin binding is Ca²⁺ dependent. Glutamatergic postsynaptic clustering was more readily disrupted by the mutagenesis than GABAergic postsynaptic protein clustering. Perhaps neurexins-neuroligins, or neurexin-1 at least, is most important for GABA synapse formation or controlling the balance of GABA and glutamate synapses. These results suggest that differential neurexin-neuroligin binding affinities and splice variations may play an instructive role in postsynaptic differentiation.

Key words: synaptogenesis; neuroligin; glutamate; GABA; gephyrin; PSD-95; postsynaptic

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Received March 31, 2005; revised March 13, 2006; accepted March 14, 2006.

Correspondence should be addressed to Ann Marie Craig, Brain Research Centre, University of British Columbia Hospital F149, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Email: amcraig{at}interchange.ubc.ca

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