Precise Therapeutic Targeting of DistinctNRXN1+/-Mutations

Abstract

ABSTRACTAs genetic studies continue to identify risk loci that are significantly associated with risk for neuropsychiatric disease, a critical unanswered question is the extent to which diverse mutations--sometimes impacting the same gene--will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions inNRXN1, a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns ofNRXN1alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain, and are differentially impacted by unique (non-recurrent) deletions. We contrast the cell-type-specific impact of patient-specific mutations inNRXN1using human induced pluripotent stem cells, finding that perturbations inNRXN1splicing result in divergent cell-type-specific synaptic outcomes. Via distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms,NRXN1+/-deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Stratification of patients by LOF and GOF mechanisms will facilitate individualized restoration ofNRXN1isoform repertoires; towards this, antisense oligonucleotides knockdown mutant isoform expression and alters synaptic transcriptional signatures, while treatment with β-estradiol rescues synaptic function in glutamatergic neurons. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disease, our findings add nuance to future considerations of precision medicine.