Neuroligin-2 is a recently discovered component of GABA synapses. Neuroligins and their presynaptic binding partners, neurexins, can mediate calcium-dependent cell adhesion112,115. By virtue of binding the glutamate postsynaptic scaffolding molecule PSD-95116, neuroligins are thought to be critical for glutamate synapse development. However, of the 4-5 neuroligins in mammals, neuroligin-2 does not localize to glutamate synapses but rather localizes to GABA synapses, as reported in two independent studies47,117. Two other key studies also indicated a role of neuroligins in GABA synapse development. Prange et al.118 first showed that altering the levels of neuroligin-1 or PSD-95 can alter the number of GABAergic as well as glutamatergic synapses. Finally, Chih et al.119 reported that RNAi knock-down of neuroligins-1, -2, and -3, or each individually, disrupted both glutamatergic and GABAergic synapses, GABAergic more severely. Thus, neuroligin-2 may have a critical function at GABA synapses.

Structurally, neuroligins have an extracellular inactive acetylcholinesterase homologous domain that binds to the LNS domain of neurexins. Both neuroligins and neurexins terminate intracellularly in PDZ domain binding sites. Whether the PDZ domain binding site on neuroligin-2 functions at GABA synapses, or whether it is there primarily to allow cross-talk with key PDZ domain proteins at glutamate synapses is not yet clear. Neuroligins are also multimeric120. Reconciling the multimeric nature with the selective localization of neuroligin-2 would suggest that neuroligin-2 oligomerizes with itself in preference to neuroligins-1, -3, or -4. Finally, a site of alternative splicing in neuroligin-2, the "A" site in the acetylcholinesterase homologous domain121, adds further complexity, of as yet unknown functional significance.

Four functions for neuroligin-2 have been suggested, all mutually compatible: mediating adhesion between the correct pre- and post-synaptic partners, inducing or maintaining presynaptic differentiation, balancing glutamate and GABA synaptic inputs, and mediating GABAergic postsynaptic differentiation. While testing of the first hypothesis, selective synaptic adhesion, awaits in vivo knockout analyses, significant in vitro evidence exists to support the other functions.

As first shown by Scheiffele et al.122, neuroligins expressed on non-neuronal cells are able to induce presynaptic differentiation in contacting axons. These induced 'hemi-presynapses' consist of clusters of synaptic vesicles able to undergo activity-dependent recycling with properties similar to bona fide synapses, and thus must contain a fairly complete presynaptic apparatus123. Multiple neuroligins are able to induce such presynaptic differentiation in GABAergic or glutamatergic axons47. Neuroligin-induced presynaptic differentiation is mediated by aggregation of neurexin on the axon surface120. One obvious interpretation of these results is that neuroligin-2 at GABA postsynaptic sites may function to induce and/or maintain synaptic vesicle clusters and associated release apparatus in the apposing axon.

The ability of neuroligins on the dendrite to maintain apposing presynaptic specializations combined with the binding of neuroligins to PSD-95 appears to underlie their role in regulating the balance of excitatory versus inhibitory synaptic inputs124, as discussed more extensively in Chapter 5. The loss of GABA synapses observed upon overexpression of PSD-95 may occur by translocation of neuroligin-2 from GABA to glutamate synapses, thus destabilizing GABA synapses47,118,125. Whether there are conditions that induce movement of the other neuroligins to GABA synapses, or whether they can partially compensate for the function of neuroligin-2 is not yet clear.

Finally, neuroligin-2 may function within the postsynaptic side to mediate clustering of GABAA receptors and gephyrin. Graf et al.47 showed that neurexin presented to dendrites induces focal postsynaptic differentiation, forming separate clusters of GABAA receptors with gephyrin or NMDA glutamate receptors with PSD-95. Furthermore, direct aggregation of neuroligins on the dendrite surface indicated a link from all neuroligins to PSD-95 but only neuroligin-2 to gephyrin. Thus, aggregation of neuroligin-2 on the dendrite surface by neurexins on GABAergic axons may function to recruit and/or stabilize GABAA receptors and gephyrin at a developing GABAergic synapse. Supporting this idea, mislocalized expression of neuroligin or RNAi knockdown resulted in a reduction in morphological and functional GABAergic synapses47,119. Defining the molecular link between neuroligin-2, GABAA receptors, and gephyrin is an area ripe for investigation, as none of these components are reported to bind directly. The dystroglycan complex, another major known component of mature GABAergic postsynaptic sites, also does not bind any of these components directly but does bind neurexins113, thus linking it to neuroligin.

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