It is already known that the postsynaptic adhesion molecule neuroligin 1, in complex with its axonal receptor, β-neurexin, is involved in presynaptic terminal formation. Now, new research published in Science shows that the same complex is also involved in postsynaptic differentiation, and that neuroligins have an important role in maintaining the functional balance of excitatory and inhibitory synapses.

Chih and co-workers first showed that neuroligin overexpression in cultured rat hippocampal cells increased both the formation of dendritic spines and the recruitment of postsynaptic molecules, including NMDA (N-methyl-D-aspartate) receptors.

They then used two neuroligin 1 mutants to investigate the involvement of neuroligin in postsynaptic density molecule recruitment and scaffolding assembly. A dominant-negative mutant with a disrupted β-neurexin-binding site induced postsynaptic clustering of the scaffolding molecule postsynaptic density protein 95 (PSD-95), but the clusters were misaligned with the presynaptic terminals.

In the second mutant, the loss of neuroligin's PDZ-binding motif resulted in a predictable absence of PSD-95 clustering, but no severe effect on NMDA receptor clustering was seen, indicating that NMDA receptor recruitment is largely independent of PSD-95 clustering. Therefore, the PDZ-binding motif is required for PSD-95 clustering, whereas the β-neurexin-binding site is needed for the clusters to align with presynaptic terminals.

In rodents, there are three neuroligin isoforms, and knockdown of each single isoform resulted in a significant reduction in the number of excitatory and inhibitory terminals. This indicates that there is some functional overlap between the neuroligin isoforms.

Chih et al. also found that excitatory and inhibitory neurotransmission were not equally perturbed by neuroligin downregulation — inhibitory neurotransmission was affected far more than excitatory neurotransmission, which resulted in an imbalance of cellular activity. So far, the reasons for this preferential effect on inhibitory transmission are unknown, but the authors suggest that excitatory synapses might be better able to produce a compensatory upregulation in activity. Moreover, at normal neuroligin levels, a significant proportion of excitatory synapses are silent, and loss of these synapses will not alter cellular excitation.