RESEARCH HIGHLIGHTS

SYNAPTOGENESIS Neurexins and new synapses DOI: 10.1038/nrn1939 depends on the Neurexins are a set of transmem- ing of the glutamatergic postsynaptic clustering of postsynaptic proteins in brane cell adhesion molecules that protein PSD-95 and 1, 3 URLs line with the appropriate presynaptic reside on the presynaptic membrane and 4. By contrast, clustering of the axon terminals. In the formation of and comprise six main isoforms GABAergic postsynaptic proteins both glutamate- and GABA (γ-ami- and numerous naturally occuring gephyrin and 2 was unaf- nobutyric acid)-containing synapses splice variants. It is possible that fected. this process relies on interactions presynaptic expression of specific Moreover, the addition of the S4 between presynaptic neurexins and neurexin isoforms promotes develop- insert significantly decreased binding postsynaptic neuroligins. Writing in ment of specific types of postsynaptic between neurexin 1β and neuroligin The Journal of Neuroscience, Craig machinery. However, all six isoforms 1, whereas neurexin 1β and neuroli- and colleagues report that the expres- are expressed in a differential but gin 2 binding remained unaffected. sion of differentially spliced variants overlapping fashion in different This indicates that the formation (leading to the formation of different classes of , which indicates of glutamatergic synapses is more mature mRNA molecules and there- that the type of presynaptic isoform sensitive than GABAergic synapse fore different proteins) of neurexins is not likely to regulate the assembly development to modifications in influences the types of synapse that of different types of postsynaptic β-neurexin splicing. develop by altering neurexin–neuro- machinery. Nevertheless, there is a These findings support the idea ligin binding affinities. single splice site (splice site 4, or S4) that neurexin splice variations are on β-neurexins, located on the LNS important for maintaining the bal- (, neurexin, sex hormone- ance between the development of binding protein) domain, that is both excitatory and inhibitory synapses. necessary and sufficient for synap- It will be interesting to determine togenesis, and so deserves particular whether such splice variations consideration. affect neurotransmitter-specific Craig and co-workers investi- synaptogenesis throughout brain gated the effects on the interactions development. between neurexins and neuroligins Alison Rowan of adding a 30 amino acid insertion at S4 on neurexin 1β. The results ORIGINAL RESEARCH PAPER Graf, E. R. et al. Structure function and splice site analysis of the revealed a complex picture: rather synaptogenic activity of the neurexin-1/βLNS than simply disrupting neurexin– domain. J. Neurosci. 26, 4256–4265 (2006) neuroligin binding, addition of the FURTHER READING Graf, E. R. et al. Neurexins induce differentatiation of GABA and glutamate S4 inserts impaired the development postsynaptic specializations via neuroligins. Cell of glutamatergic but not GABAergic 119, 1013–1026 (2004) synapses. Specifically, the S4 inser- Hippocampal cluster neuroligin 2 (red) on dendrites at sites of contact with co-cultured COS cells expressing neurexin 1β containing the splice site 4 insert tion led to a reduction in the cluster- (blue). The induced clusters of GABAergic postsynaptic components lack synapsin (green), unlike interneuronal synapses. Image courtesy of Y. Kang, X. Zhou and A. M. Craig, University of British Columbia, Canada.

NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JUNE 2006 | 1