Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Abstract

Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, that thereby determines the precise responses of synapses to spike patterns in a neuron and circuit, and that is vulnerable to impairments in neuropsychiatric disorders.

Subsynaptic spatial organization as a regulator of synaptic strength and plasticity

“…2). CAMs include a large number of protein families, and some members directly interact with glutamate receptors and scaffolds [49]. Cadherin family members adopt a perisynaptic distribution, and recent EM and super-resolution imaging has revealed nanoclustered organizations of several CAMs including SynCAM [50], neuroligin and LRRTM2 [51], and Neurexin1β [52].…”

Structures of neurexophilin–neurexin complexes reveal a regulatory mechanism of alternative splicing

“…Neurexins (Nrxns) are a family of presynaptic cell-adhesion molecules that are important for specifying the functional properties of synapses (Südhof, 2017). Neural circuits are, in turn, composed of neurons that communicate with each other at synapses.…”

“…Neurexins (Nrxns) are a family of presynaptic cell-adhesion molecules that are important for specifying the functional properties of synapses (Südhof, 2017). Through their interactions with various binding partners, neurexins constitute part of a molecular code and act as hub molecules to organize and regulate synaptic function (Südhof, 2017). Neurexins are encoded by three genes (Nrxn1-3 in mice), each of which contains multiple promoters to drive expression of Nrxn1a-3a, Nrxn1b-3b, and Nrxn1c.…”

“…to Fc tags, were unable to co-precipitate LNS2, suggesting that the complete mature fragment of Nxph1 represents the minimal LNS2binding region of Nxph1 . While alternative splicing of neurexins has dramatic effects on their interactions with ligands (Südhof, 2017), no structural data explain how alternative splicing regulates these interactions at the atomic level. For example, Nrxn1b lacking an insert in SS4 has a higher binding affinity for neuroligin-1 (Nlgn1) than Nrxn1b containing an insert in SS4 (Boucard et al, 2005;Comoletti et al, 2006;Shen et al, 2008;Elegheert et al, 2017), but the structural basis for this regulatory effect is unknown.…”

Stress-induced neuron remodeling reveals differential interplay between neurexin and environmental factors

“…We identified the singular C. elegans ortholog of human neurexins, nrx-1, to be required in the DVB neuron for this neurite outgrowth. Neurexins are synaptic adhesion molecules with diverse functions in synaptic formation, maturation, maintenance, function, and plasticity (Sudhof, 2017), and have been genetically associated with both ASDs and schizophrenia (Gauthier et al, 2011;Kirov et al, 2009;Reichelt, Rodgers, & Clapcote, 2012). Therefore, neurexins are strong candidates for mediating changes in neuron morphology and behavior in response to environmental stress.…”