Does mutation in neurexin drive the pathogenesis of schizophrenia?

Synapses are the fundamental computational unit of the brain. Neurexins (NRXN) are a class of synaptic proteins, mutations in which have been linked to the pathogenesis of schizophrenia. The precise role of NRXN1 mutations in schizophrenia phenotypes is an area under active investigation, as reported at WFSBP Virtual 2021. 

In 2013, Professor Thomas C. Südhof, Stanford University School of Medicine, United States was awarded the Nobel Prize for his discovery of the molecular machinery that regulates vesicular traffic in neurons. In this plenary lecture, Professor Südhof explained his work on the genes, molecules and pathways involved in the pathogenesis of schizophrenia, one focus of which is neurexin.

Neurexins were initially discovered as a component of the black widow spider venom that allows her to paralyse small prey by causing excessive neurotransmitter release. It is now known that neurexins are a family of cell-surface proteins and are central regulators of all synapses. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, particularly schizophrenia, autism and Tourette syndrome.

NRXN1 mutation is the most common single gene mutation linked to schizophrenia

Heterozygous mutations in the neurexin gene (NRXN1) are rare (found in less than 0.2% of patients with schizophrenia). However, NRXN1 mutation is the most common single gene mutation linked to schizophrenia, and has been shown to directly impair synaptic function in human neurons.1

 

Do NRXN1 mutations predispose to schizophrenia?

More than 90% of NRXN1 mutations are associated with psychiatric disorders, but the same mutation can cause different clinical presentations.2 This raises questions about the precise role of NRXN1 mutations in psychiatric disorders and whether or not there are other genes involved that push the clinical presentation in a particular direction. In line with these ideas, NRXN1 polymorphisms have been associated with differential responses to antipsychotic medication in patients with schizophrenia.1

NRXN1 polymorphisms are associated with differential responses to antipsychotic medication in patients with schizophrenia

Studies in human neurons show that NRXN1 mutations act to impair neurotransmitter release across the synapse as well as increasing neuronal calcium/calmodulin-dependent serein protein kinase (CASK) levels, a scaffolding protein that is critical for normal brain function.1

There appears to be a distinct phenotype of NRXN1 mutation that likely reflects impairment of a specific step in synaptic transmission, and this may be amenable to pharmacological intervention said Professor Südhof.

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Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Pak C, et al. Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1. Cell Stem Cell. 2015;17:316-28
  2. Decipher Database. Available at https://www.deciphergenomics.org/gene/NRXN1/overview/clinical-info. Accessed July 2021
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