Neurexins: molecular codes for shaping neuronal synapses

Abstract

Nervous systems represent remarkable examples of a highly organized tissue with an abundance of specialized cells in an intricate structure. During development, neuronal connectivity arises from a series of steps, including cell specification, migration, targeted growth, synapse formation and remodelling. Spontaneous activity and sensory experience propagated through the developing networks play a significant role in organizing aspects of neuronal wiring. However, many fundamental steps of neuronal morphogenesis and synapse formation proceed normally even in the absence of neurotransmission [1][2][3] . Thus, genetically encoded programmes are thought to orchestrate key aspects of the timing and dynamics of neuronal growth and nervous system wiring [4][5][6][7] . Cell surface adhesion and signalling molecules significantly contribute to all of these developmental steps. Thus, each neuronal cell type carries an array of cues linked to cellular origin and cell fate that are integral to its developmental specification. Although signalling processes, neuronal activity and disease states may shift these codes, there are constraints that restrict this plasticity, thereby maintaining cell type-specific properties. One critical and extensively studied process in nervous system development is the selective growth and targeting of neurites, which encompasses axon guidance and synaptic specificity 7,8 . The present Review aims to discuss a second key aspect of neuronal wiring: the molecular principles of neuronal synapse formation and the specification of synapse function. We will use the Neurexin family, one class of cell adhesion molecules, to illustrate the fundamental principles of this process that likely apply to many other adhesion systems operating at neuronal synapses.Adhesive modules for synapse assembly. Synaptic differentiation relies on a large number of synaptic adhesion and signalling molecules with so-called synaptogenic properties, that is, the ability of an isolated factor to trigger a substantial degree of the synaptic differentiation process. When presented in non-neuronal cells or on synthetic surfaces, synaptogenic proteins nucleate the formation of functional presynaptic or postsynaptic assemblies 9-12 . For example, postsynaptic adhesion molecules of the Neuroligin family trigger the assembly of functional presynaptic terminals in axons through interaction with their receptor Neurexin 9,10 (Fig. 1a). Conversely, Neurexin-mediated clustering of Neuroligins triggers the recruitment of NMDA-type glutamate receptors and scaffolding molecules 12,13 . This early cell biological analysis uncovered fundamental activities of Neurexin proteins and their ligands. Subsequent genetic studies then probed the functional consequences of inactivating Neurexin genes in various model organisms (see below). What makes the roles for Neurexins in this process so fascinating is twofold. First, the Neurexin gene family encodes a vast array of distinct transcript isoforms generated from multiple genes (Nrxn1, Nrxn2, Nrxn3), a...

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“…Synapses are the sites where two neurons physically connect and communicate with each other, and they are the most basic unit of the brain network. 106 Each synapse is formed by thousands of proteins and can change its composition and signal processing…”

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“…Neurexins are presynaptic cell-adhesion molecules that play crucial role in defining synapse properties through differential interactions with multifarious extra-and intra-cellular ligands. Genetic perturbation of neurexins and their ligands are implicated in multiple neuropsychiatric disorders (Sudhof, 2017;Kasem et al, 2018;Gomez et al, 2021). Neurexin genes (Nrxn1, Nrxn2, and Nrxn3 in mice) use alternative promotors to transcribe distinct isoforms (α, β, γ), whose mRNAs are subject to extensive alternative splicing in patterns that are specific to neuronal cell types (Treutlein et al, 2014;Fuccillo et al, 2015;Furlanis et al, 2019;Lukacsovich et al, 2019).…”

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“…Because of this particular composition, they transmitted information between neurons effectively [121]. Newly formed synapses were not static, as they underwent constant change in order to meet their behavioral needs in a constantly changing environment [122]. These changes could be in the formation of new synapses or in the enhancement of synaptic efficacy known as synaptic plasticity [123].…”