Postsynaptic neuroligin enhances presynaptic inputs at neuronal nicotinic synapses

Abstract

Neuroligins are cell adhesion molecules that interact with neurexins on adjacent cells to promote glutamatergic and GABAergic synapse formation in culture. We show here that neuroligin enhances nicotinic synapses on neurons in culture, increasing synaptic input. When neuroligin is overexpressed in neurons, the extracellular domain induces presynaptic specializations in adjacent cholinergic neurons as visualized by SV2 puncta. The intracellular domain is required to translate the SV2 puncta into synaptic input as reflected by increases in the frequency of spontaneous mini-synaptic currents. The PDZ-binding motif of neuroligin is not needed for these effects. Together, the extracellular and proximal intracellular domains of neuroligin are sufficient to induce presynaptic specializations, align them over postsynaptic receptor clusters, and increase synaptic function. Manipulation of endogenous neuroligin with beta-neurexin-expressing cells confirms its presence; repressing function with dominant negative constructs and inhibitory shRNA shows that endogenous neuroligin helps confer functionality on existing nicotinic synaptic contacts. Endogenous neuroligin does not appear to be required, however, for initial formation of the contacts, suggesting that other components under these conditions can also initiate synapse formation. The results indicate that postsynaptic neuroligin is important for functional nicotinic synapses on neurons and that the effects achieved will likely depend on neuroligin levels.

Minimal aberrant behavioral phenotypes of neuroligin‐3 R451C knockin mice

“…Our findings of generally normal developmental milestones, physical attributes, simple procedural abilities, and complex behavioral traits in NL3 may be viewed in the broader context of the multiple neurexin and neuroligin proteins and the specific binding of their splice variants during synaptic formation (Chih et al, 2005;Chubykin et al, 2005;Varoqueaux et al, 2006;Budreck and Scheiffele, 2007;Chubykin et al, 2007;Conroy et al, 2007;Craig and Kang, 2007;Levinson and El-Husseini, 2007;Sheng and Hoogenraad, 2007). Reduction in the cell surface expression of the neuroligin-3 protein may not be sufficient to affect a large number of synapses relevant to social and cognitive abilities, if other neuroligins remain available.…”

“…Neurexins in axons bind to neuroligins in dendrites at synaptic junctions to trigger synaptic differentiation (Chubykin et al, 2005;Varoqueaux et al, 2006;Arac et al, 2007;Budreck and Scheiffele, 2007;Chubykin et al, 2007;Conroy et al, 2007;Craig and Kang, 2007). Mutations in neuroligin-3 (NL3) are reported to shift the balance between glutamatergic and GABAergic synapses (Chih et al, 2005;Chubykin et al, 2005;Levinson and El-Husseini, 2007;Sheng and Hoogenraad, 2007).…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…Functionally, the neurexin-1 regulates targeting of 42 nAChRs to pre-synaptic terminals in neurons (Cheng et al, 2009). Complementary studies report a role for neurexin-1 and neuroligin-1 in recruitment of 3-containing nAChRs to the postsynaptic density (Conroy et al, 2007;Ross & Conroy, 2008). In addition, recent studies show that neurexins interact with multiple receptors.…”

Induction of GABAergic Postsynaptic Differentiation by α-Neurexins

“…Overexpression or knockdown of neuroligins in cultured neurons also affects synapse development, altering the function and ratio of excitatory and inhibitory synapses (22)(23)(24)(25). A role for neuroligin in development of neuronal cholinergic synapses has also recently been found (26).…”