Genetic insights and neurobiological implications from NRXN1 in neuropsychiatric disorders

Many neuropsychiatric and neurodevelopmental disorders commonly share genetic risk factors. To date, the mechanisms driving the pathogenesis of these disorders, particularly how genetic variations affect the function of risk genes and contribute to disease symptoms, remain largely unknown. Neurexins are a family of synaptic adhesion molecules, which play important roles in the formation and establishment of synaptic structure, as well as maintenance of synaptic function. Accumulating genomic findings reveal that genetic variations within genes encoding neurexins are associated with a variety of psychiatric conditions such as schizophrenia, autism spectrum disorder, and some developmental abnormalities. In this review, we focus on NRXN1, one of the most compelling psychiatric risk genes of the neurexin family. We performed a comprehensive survey and analysis of current genetic and molecular data including both common and rare alleles within NRXN1 associated with psychiatric illnesses, thus providing insights into the genetic risk conferred by NRXN1. We also summarized the neurobiological evidences, supporting the function of NRXN1 and its protein products in synaptic formation, organization, transmission and plasticity, as well as disease-relevant behaviors, and assessed the mechanistic link between the mutations of NRXN1 and synaptic and behavioral pathology in neuropsychiatric disorders.