Precise Therapeutic Targeting of DistinctNRXN1^+/-Mutations

Abstract

As 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 common or individually tailored therapeutic strategies. Here we consider this in the context of rare, heterozygous, and non-recurrent copy number variants (2p16.3) linked to a variety of neuropsychiatric disorders that impactNRXN1, 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 patient-specific (non-recurrent) deletions. Progress towards precision medicine may require restoring each person’sNRXN1isoform repertoires in a cell-type-specific manner. Towards this, here we contrast the cell-type-specific impact of unique patient-specific mutations inNRXN1using human induced pluripotent stem cells. Perturbations inNRXN1splicing causally lead to divergent cell-type-specific synaptic outcomes: whereasNRXN1+/−deletions result in a decrease in synaptic activity throughout glutamatergic neuron maturation, there is an unexpected increase in synaptic activity in immature GABAergic neurons. Both glutamatergic and GABAergic synaptic deficits reflect independent loss-of-function (LOF) and gain-of-function (GOF) splicing defects. Towards clinical relevance, we show that treatment with β-estradiol increasesNRXN1expression in glutamatergic neurons, while antisense oligonucleotides knockdown mutant isoform expression across both glutamatergic and GABAergic neurons. Direct or indirect manipulation ofNRXN1splicing isoforms provides a promising therapeutic strategy for treating humans with 2p16.3 deletions.