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LRRTM2 controls presynapse nano-organization and AMPA receptor sub-positioning through Neurexin-binding interface

ABSTRACT: Synapses are organized into nanocolumns that control neurotransmission efficacy through precise alignment of postsynaptic AMPARs and presynaptic release sites. How these are trans-synaptically arranged remains elusive, despite evidence involving adhesion proteins. Highly enriched and confined at synapses, Leucine-Rich Repeat Transmembrane protein LRRTM2, is ideally poised to play this role by interacting with presynaptic Neurexins. Recent evidence show that LRRTM2 interacts with Neurexins through the C-terminal cap of LRRTM2 extracellular domain, but the role of this binding interface containing E348 has not been explored in synapse formation and function. Here, we developed a conditional knock-out mouse model (cKO) to address these questions and iden-tify LRRTM2 as a critical regulator of synapse nano-organization. We show that LRRTM2 cKO specifically impairs excitatory synapse formation and function. Surface expression, synaptic clustering, and membrane diffusion are tightly controlled by different motifs in LRRTM2 C-terminal domain, while the N-terminal domain controls pre-synapse nano-organization, AMPARs sub-positioning and stabilization, through the recently identified Neurexin-binding interface. Thus, LRRTM2 appears as a central organizer of synapse nanostructure through interaction with presynaptic Neurexins.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Stephane Claverol

LAB HEAD: Stephane Claverol

PROVIDER: PXD054623 | Pride | 2024-09-18

REPOSITORIES: Pride

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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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LRRTM2 controls presynapse nano-organization and AMPA receptor sub-positioning through Neurexin-binding interface

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