Allele-specific rescue of neurexin behavioral phenotypes by monoamine-targeting compounds

Neurexins are synaptic adhesion molecules associated with vast neurologic changes in humans, including neurodevelopmental delay, autism, schizophrenia, Tourette syndrome, and seizures. The NRXN1 gene produces >100 protein isoforms through alternative promoters and extensive splicing, which are differentially impacted by NRXN1 deletions found in patients. Yet pharmacologic targeting of NRXN1 isoforms or deletions has not been comprehensively studied. Here, we developed a behavioral screening approach in C. elegans to identify small molecule compounds that modify decreased activity levels caused by isoform-specific deletions of neurexin (nrx-1). Screening 190 compounds, we discovered that monoamine-targeting drugs differentially improve behavioral phenotypes depending on which nrx-1 isoforms are disrupted. Broad modulation of monoamine signaling or antagonism of specific serotonin receptors are required to increased activity of both alleles tested. Modulation of adrenergic signaling uniquely improved loss of α-isoform, and additional antagonism of dopamine signaling was required to increase activity with loss of γ isoform. The FDA-approved atypical antipsychotic olanzapine was the sole validated compound achieving Z-scores >2 in both screens. In Drosophila Nrx-1 mutants, olanzapine, but not the related compound asenapine maleate, significantly improved activity deficits, demonstrating evolutionary conservation of the neurexin-monoamine relationship. Multi-behavior testing revealed pharmacological specificity: olanzapine improved both activity and social feeding phenotypes of nrx-1 alleles, while asenapine maleate improved activity, but worsened social feeding, indicating distinct modifier impacts across behavioral domains. Our findings establish monoamine modulation as a conserved compensatory mechanism for neurexin loss, identify olanzapine as a lead compound for targeting neurexin loss, and demonstrate that allele stratification and pharmacogenomic approaches are needed for precision intervention in behavioral conditions.