Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

Abstract

Synapses serve as the interface for the transmission of information between neurons in the central nervous system. The structural and functional characteristics of synapses are highly dynamic, exhibiting extensive plasticity that is shaped by neural activity and regulated primarily by trans-synaptic cell-adhesion molecules (CAMs). Prototypical trans-synaptic CAMs, such as neurexins (Nrxs) and neuroligins (Nlgs), directly regulate the assembly of presynaptic and postsynaptic molecules, including synaptic vesicles, active zone proteins, and receptors. Therefore, the trans-synaptic adhesion mechanisms mediated by Nrx–Nlg interaction can contribute to a range of synaptopathies in the context of pathological pain and other neurological disorders. The present review provides an overview of the current understanding of the roles of Nrx–Nlg interaction in the regulation of trans-synaptic connections, with a specific focus on Nrx and Nlg structures, the dynamic shaping of synaptic function, and the dysregulation of Nrx–Nlg in pathological pain. Additionally, we discuss a range of proteins capable of modulating Nrx–Nlg interactions at the synaptic cleft, with the objective of providing a foundation to guide the future development of novel therapeutic agents for managing pathological pain.

Associative memory neurons of encoding multi-modal signals are recruited by neuroligin-3-mediated new synapse formation

“…If the synapse formation is required for the recruitment of associative memory neurons, the linkage of presynaptic boutons and postsynaptic spines is expectedly needed. Neuroligin-3 as one of the linkage proteins ( Craig and Kang, 2007 ; Li et al, 2022 ; Lisé and El-Husseini, 2006 ; Südhof, 2017 ; Uchigashima et al, 2021 ) for synapse fixations has been examined, in which short-chain RNA (shRNA) specific for neurolingin-3 ( Chang et al, 2006 ; Khatri et al, 2012 ; Pardridge, 2007 ; Pushparaj et al, 2008 ; Rao et al, 2009 ) was microinjected into the barrel cortex. Subsequently after the associative learning paradigms, the formation of associative memory, the innervation of new synapses, as well as the recruitment of associative memory neurons in the barrel cortex were examined by behavioral tasks, neural tracing morphologically and electrophysiological recording functionally.…”

A Genome-wide Association Study Identifies Novel Genetic Variants Associated with Neck or Shoulder Pain in the UK Biobank (N = 441,757)

“…Secondly, CA10 may play the role of adaptors, facilitating neurexins' indirect connections with unidentified postsynaptic target molecules, and thus mediating the development of new transsynaptic complexes (Sterky et al 2017). Evidence suggests that the mechanism by which regulatory proteins interact with neurexins-neuroligins to jointly form intersynaptic bridges plays a role in pathological pain (Li et al 2022). As there are not many studies on CA10 in humans, future studies should focus on elucidating the mechanism of CA10 action on neck or shoulder pain.…”

Associative memory neurons of encoding multi-modal signals are recruited by neuroligin-3 mediated new synapse formation

“…The microtubule prolongation and the synapse formation require activity-dependent epigenetic events from microRNA-324 and microRNA-133a [3,22,23]. As we known, the formation of new synapses is followed by the linkage and fixation of presynaptic and postsynaptic membranes through linkage proteins, such as neuroligin, neurexin, N-cadherin, ephrin, and so on [32][33][34][35][36]. In the present study, we have studied the requirement of neuroligin-3 for the synapse linkage and 39 fixation.…”

“…If the synapse formation is required for the recruitment of associative memory neurons, the linkage of presynaptic boutons and postsynaptic spines is expectedly needed. Neuroligin-3 as one of the linkage proteins [32][33][34][35][36] for synapse fixations has been examined, in which short-chain RNA (shRNA) specific for neurolingin-3 [37][38][39][40][41] was microinjected into the barrel cortex.…”

“…The study of molecular mechanism for the recruitment of associative memory cells: In the study of the role of neuroligin-3, one of the proteins for synapse linkage [32][33][34][35][36], in the formation of new synapse innervations and the recruitment of associative memory cells in the barrel cortex, the approach of mRNA knockdown was applied by the short-hairpin RNA (shRNA) specifically for neuroligin-3 mRNA that was carried by adeno-associated viruses (AAV) and was microinjected in this cortical area [37][38][39][40][41]. The microinjections of AAV-DJ/8-U6-mNlgn3-GFP (pAAV[shRNA]-U6-mNlgn3-EGFP) into the barrel cortex were done three days prior to the training paradigm of associative learning.…”