Role Of Neuroligin Binding To Neurexins In Synaptic Organization

Richard Fairless, Carsten Reissner, and Markus Missler*

1. SUMMARY

The complex formed by the synaptic cell adhesion molecules neuroligin and P-neurexin has been implicated in synaptogenesis due to the molecular asymmetry of their heterophilic binding, reflecting the asymmetric nature of the synapse. During the past 5 years, their role in synapse formation has been explored in vitro, yielding exciting, though sometimes conflicting results. In this chapter, we focus on the biochemical and functional aspects of the neuroligin/p-neurexin complex, with an emphasis on the recent contributions coming from various cell culture approaches. In addition, we point out important unresolved issues with respect to their binding properties, their proposed function at excitatory versus inhibitory synapses, and their putative involvement in psychiatric diseases such as autism spectrum disorders.

2. INTRODUCTION

The first demonstration that neuroligins could bind to neurexins came in 1995 with their discovery by affinity chromatography on immobilized p-neurexin1. It was shown that all three rat neuroligins interacted with the extracellular domain of neurexin 1p in a calcium-dependent manner, and that this interaction was also dependent upon the splice variation of P-neurexin. Neurexins 1P, 2P, and 3P were all able to interact with neuroligins in biochemical and cell culture-binding assays, but only when P-neurexins were lacking an insert in splice site #4 (1,2; but see ref. 3 for binding of a particular splice variant of neuroligin to all neurexins). Since its discovery, the neuroligin/P-neurexin complex has been suggested to play a role in

'Center for Physiology, Georg-August University Göttingen, Humboldtallee 23, 37073 Göttingen, Germany; [email protected]

synapse formation and/or maturation. This was subsequently supported by the complex ability to mediate cell-cell adhesion4, the postsynaptic location5 and interactions of neuroligin6, and by high expression levels of neuroligin and P-neurexin mRNAs during rapid synaptogenesis in the brain6.

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