Distinct Synaptic Mechanisms Drive NRXN1 Variant-Mediated Pathogenesis in iPSC-Derived Neuronal Models of Autism and Schizophrenia

Copy number deletions in the 2p16.3/NRXN1 locus confer genome wide risk for autism spectrum disorder (ASD) and schizophrenia (SCZ). Prior work demonstrated that heterozygous NRXN1 deletions decreases synaptic strength and neurotransmitter release probability in human-iPSC derived cortical glutamatergic induced neurons and this synaptic phenotype is replicated in SCZ patient iPSCs with varying NRXN1 genomic deletions. What is unknown, however, is whether similar synaptic impairment exists in ASD patients carrying NRXN1 deletions. Answering this question is important to determine whether all NRXN1 deletion carriers should be treated similarly or individually, based on their genetic backgrounds and deletion breakpoints. Here, using previously uncharacterized ASD patient iPSC lines, we show that ASD-NRXN1 deletions impact cortical synaptic function and plasticity in unique ways compared to SCZ-NRXN1 deletions. Specifically, at a single neuronal level, ASD-NRXN1 deletions alter basal spontaneous synaptic transmission by selectively enhancing excitatory synaptic signaling with no changes at inhibitory synapses while SCZ-NRXN1 deletions reduce both excitatory and inhibitory synaptic transmission. At the neuronal network level, there exists enhanced transmission probability and irregular firing patterns in ASD-NRXN1 deletions. Such changes at the synaptic and network level connectivity patterns influence a critical form of developmental cortical plasticity, synaptic scaling, as ASD-NRXN1 deletions uniquely fail to upscale their synaptic strength in response to chronic neuronal silencing. Together, these findings highlight the disorder-specific consequences of NRXN1 deletions on synaptic function and connectivity, offering mechanistic insights with implications for therapeutic targeting and refinement strategies for NRXN1-associated synaptopathies. HighlightsO_LINovel ASD patient-iPSC-derived E-I culture model to investigate pathogenic NRXN1 deletions on cortical synaptic function and plasticity C_LIO_LIASD-NRXN1 deletions enhance basal synaptic transmission by specifically increasing excitatory neurotransmitter release, opposite of SCZ-NRXN1 deletions C_LIO_LISynaptic scaling homeostasis is impaired in ASD-NRXN1 deletions C_LIO_LISpike train cross-correlation analysis reveals increased transmission probability and irregular firing patterns in ASD-NRXN1 deletions C_LI