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A Specific Neuroligin3-αNeurexin1Signaling Regulates GABAergic Synaptic Function in Mouse Hippocampus

ABSTRACT: Synapses are fundamental organizers of precise signal propagation between neurons. Maintaining synapse assemblies require interactions between pre- and post- synaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the function of Neuroligins (Nlgn1 - 4), postsynaptic CAMs, relies on the formation of trans-synaptic complexes with Neurexins (Nrxs), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated through Nrx interaction is mostly unknown. Here, we find for the first time that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3 (VGT3)-expressing inhibitory terminals. Overexpression and knockdown approaches indicate that Nlgn3 regulates VGT3-positive inhibitory interneuron-mediated synaptic transmission. Fluorescent in situ hybridization and single-cell RNA sequencing studies revealed that αNrxn1 and βNrxn3 are VGT3 interneuron-specific Nrxn isoforms and the expression levels of Nrxn splice isoforms are highly diverse in VGT3 interneurons, respectively. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrx1+AS4 expressed in VGT3-positive interneurons to regulate inhibitory synaptic transmission. Our results strongly suggest that specific Nlgn-Nrx interaction generate distinct functional properties at synapses.

ORGANISM(S): Mus musculus

PROVIDER: GSE150989 | GEO | 2021/01/04

REPOSITORIES: GEO

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Project description:The prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and post-synaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains unclear. One such complex formed by immunoglobulin superfamily member 21 (IgSF21) and neurexin2α regulates GABAergic synapse development in the mouse brain, but the precise molecular mechanisms underlying this activity remain unclear. Here, we reveal that the interaction between presynaptic Nrxn2α and postsynaptic IgSF21 is a high-affinity receptor-ligand interaction and identify a binding interface in the IgSF21-Nrxn2α complex. Despite being expressed in both dendritic and somatic regions, IgSF21 preferentially regulates dendritic GABAergic presynaptic differentiation whereas another canonical Nrxn ligand, neuroligin2 (Nlgn2), regulates primarily perisomatic presynaptic differentiation. To explore mechanisms that could underly this compartment specificity, we targeted multiple signaling pathways pharmacologically while monitoring the synaptogenic activity of IgSF21 and Nlgn2. Interestingly, both IgSF21 and Nlgn2 require c-jun N-terminal kinase (JNK)-mediated signaling, whereas Nlgn2, but not IgSF21, additionally requires CaMKII and Src kinase activity. JNK inhibition diminished de novo presynaptic differentiation without affecting the maintenance of formed synapses. We further found that Nrxn2α knockout brains exhibit altered synaptic JNK activity in a sex-specific fashion, suggesting functional linkage between Nrxns and JNK in vivo. Thus, our study elucidates the structural and functional relationship of IgSF21 with Nrxn2α and distinct signaling pathways for IgSF21 and Nlgn downstream of Nrxn2α. We therefore propose a revised hypothesis that Nrxns act as molecular hubs to specify synaptic properties not only through their multiple extracellular ligands but also through distinct intracellular signaling pathways of these ligands.

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A Specific Neuroligin3-αNeurexin1Signaling Regulates GABAergic Synaptic Function in Mouse Hippocampus

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