Impact of NRXN1α Alternative Splicing Changes on Synaptic Composition

Despite more than fifty years of research, no cures for psychiatric disease exist and the standard of treatment remains unsatisfactory. Genomic studies have identified hundreds of genetic variants that confer increased risk for psychiatric disease, including both highly penetrant rare variants and common variants of small effect, some of which have been linked to alternative splicing. Neurexin genes are amongst the most highly alternatively spliced genes in the human genome; non-recurrent heterozygous mutations of neurexin-1 (NRXN1) have been repeatedly associated with schizophrenia (SZ), autism spectrum disorder (ASD), and other psychiatric disorders, while changes in NRXN3 have been linked to addiction, reward behavior and obesity. Our preliminary data developed new bioinformatic strategies to quantify the NRXN1 alternative splice repertoire, comparing control fetal and adult cortical tissue to human induced pluripotent stem cell (hiPSC)-derived neurons from NRXN1+/- cases and controls. Here, we propose to establish methods with which to evaluate the effect on synaptic composition of experimental manipulation of the NRXN1 isoform repertoire in both control and patient-derived neurons. Once established, we anticipate that these innovative methodologies will be easily applied to NRXN3 and other alternatively spliced synaptic genes linked to psychiatric disease. Our overall objective is to resolve how changes in alternative splicing impact synaptic function - across donors, cell-types and drug exposures. Ultimately, we hope to directly correlate genomic and functional deficits across increasingly refined populations of patient-derived neurons.