Targeted Splicing Approach for Alleviation of a Neurexin 1 Haploinsufficiency Model

Abstract

NRXN1 encoding the synaptic organizing protein neurexin 1 (Nrxn1) is among the strongest risk genes for autism spectrum disorders as well as other neuropsychiatric disorders. The most common contributing mutation is a deletion in one allele. While mice lacking one form of the protein, Nrxn1$α$, have been characterized, information is lacking on animal models with heterozygous deletion of all isoforms, as well as on therapeutic approaches directly targeting Nrxn1. We report that Nrxn1+/- mice with a deletion affecting all isoforms, $α$, $β$ and $γ$, show deficits in excitatory synaptic transmission affecting presynaptic and postsynaptic properties at hippocampal CA3-CA1 synapses, and show increased repetitive behaviors. Based on previous studies indicating that exclusion of the insert at Nrxn1 splice site 5 (S5) boosts synaptic transmission, we tested S5 exclusion as a therapeutic approach. Genetic exclusion of S5 in the remaining Nrxn1 allele alleviated the deficits, restoring miniature excitatory postsynaptic current frequency, paired pulse ratio, AMPA/NMDA ratio, and repetitive behaviors to wild type levels and partially restoring Nrxn1 protein level in Nrxn1$Δ$S5/- compared to Nrxn1+/- mice. These data suggest that S5 exclusion may be a beneficial therapeutic direction in cases of neuropsychiatric disorders involving NRXN1.