Neurexins constitute a family of presynaptic transmembrane molecules that interact with postsynaptic cell adhesion molecules, most notably neuroligins. Mutations in both neurexin and neuroligin genes have been found to be associated with risk for autism spectrum disorders (ASDs). Yet despite years of intensive study, the precise function and mechanisms of these synaptic cell adhesion molecules remain elusive.

In mammals, neurexin is encoded by three distinct genes (NRXN1, NRXN2 and NRXN3).

These genes are among the most highly spliced in the genome, leading to the total expression of more than 4,000 different isoforms. The major commonality shared between every one of these neurexin isoforms is an invariant intracellular domain that is thought to transduce extracellular neurexin activation into intracellular recruitment of presynaptic components. However, very little is known about the mechanisms by which this neurexin “common denominator” mediates presynaptic assembly. A better understanding of the molecular mechanisms of this signaling cascade may lead to the development of therapeutics for a multitude of neurexin-associated ASDs.

The complexity of the mammalian genome and brain, coupled with the lethality of constitutive neurexin gene knockouts, has made it difficult to identify core components of this signaling cascade. To overcome these hurdles, Peri Kurshan’s team has chosen to approach this problem using a simplified in vivo system, the nematode C. elegans, which has only a single neurexin gene and a simple and stereotyped pattern of neuronal connectivity. Using C. elegans, Kurshan and her colleagues have found that the intracellular domain of neurexin alone can function in the absence of trans-synaptic binding¹ (and unpublished data), upending current dogma.

In the current project, Kurshan’s lab plans to use a recently developed proteomics approach² to identify the proteins responsible for neurexin’s intracellular signaling pathway. Employing novel proximity labeling methods, they will identify proteins likely to interact with neurexin’s intracellular domain. Furthermore, using a single-synapse calcium imaging technique they are developing, they will determine the functional repercussions of the loss of neurexin and of its downstream signaling pathway components.

Together, these cutting-edge approaches will lead to a comprehensive understanding of the “common denominator” of neurexin signaling, with the goal of identifying shared therapeutic targets for ASDs that result from a variety of different neurexin genetic mutations.