Neurexins and their ligands at inhibitory synapses

Abstract

Since the discovery of neurexins (Nrxns) as essential and evolutionarily conserved synaptic adhesion molecules, focus has largely centered on their functional contributions to glutamatergic synapses. Recently, significant advances to our understanding of neurexin function at GABAergic synapses have revealed that neurexins can play pleiotropic roles in regulating inhibitory synapse maintenance and function in a brain-region and synapse-specific manner. GABAergic neurons are incredibly diverse, exhibiting distinct synaptic properties, sites of innervation, neuromodulation, and plasticity. Different classes of GABAergic neurons often express distinct repertoires of Nrxn isoforms that exhibit differential alternative exon usage. Further, Nrxn ligands can be differentially expressed and can display synapse-specific localization patterns, which may contribute to the formation of a complex trans-synaptic molecular code that establishes the properties of inhibitory synapse function and properties of local circuitry. In this review, we will discuss how Nrxns and their ligands sculpt synaptic inhibition in a brain-region, cell-type and synapse-specific manner.

Human iPSC-derived cell grafts promote functional recovery by molecular interaction with stroke-injured brain

“…Fig 14). These pathways have been associated with neuronal regeneration, synapse plasticity, dendritic arborization and axon guidance [44][45][46][47] .…”

The Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses

“…However, the mechanisms and molecules that enable synapses to be formed in the first place are poorly understood. Recent insights into synapse formation came from the study of synaptic adhesion molecules, such as neurexins, neuroligins, or adhesion GPCRs (aGPCRs) (reviewed in Südhof 2017, Cao and Tabuchi 2017, Südhof 2018, Sanes and Zipursky 2020, Gomez et al 2021, Fuccillo and Pak 2021, Boxer and Aoto 2022, Cortés et al 2023). Adhesion GPCRs are characterized by a combination of a large extracellular N-terminal region containing a variety of adhesion domains, a so-called GAIN-domain that mediates autoproteolysis and is invariably found in Adhesion GPCRs, a canonical 7 transmembrane domain typical for all GPCRs, and a rather long cytoplasmic region (reviewed in Hamann et al 2015, Vizurraga et al 2020, Rosa et al 2021, Einspahr and Tilley 2022, Liebscher et al 2022, Seufert et al 2023).…”

“…In the hippocampus, Lphn2 and Lphn3 mediate excitatory synapse formation onto different subcellular regions of CA1 pyramidal neurons independent of one another (Sando et al 2019), whereas in the cerebellum Lphn2/3 act redundantly in parallel-fiber synapse formation (Zhang et al 2020). Such “molecular codes” are also employed by other synaptic adhesion molecules, such as neurexins or neuroligins (summarized in Südhof 2017, Cao and Tabuchi 2017, Südhof 2018; Sanes and Zipursky 2020, Gomez et al 2021, Fuccillo and Pak 2021, Boxer and Aoto 2022, Cortés et al 2023). It is essential to investigate how each synaptic adhesion molecule contributes to synapse formation in order to generate a comprehensive view of the intricate complexity of neuronal connections in the brain.…”

Conserved autism-associated genes tune social feeding behavior inC. elegans

“…Mutations in these genes in rodents alter motor activity, anxiety-like (avoidance) behavior, social approach and memory, performance of stereotyped behavior, and prepulse inhibition [51][52][53][54][55][56][57][58] . Neurexin mutation also impacts chemical synapse function, structure, and signaling, including presynaptic density, release probability, calcium dynamics, and post-synaptic currents [55][56][57][58][59][60][61][62] .…”