Publication date: Apr 15, 2025
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, Nrxn1α, 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 compared to Nrxn1 mice. These data suggest that S5 exclusion may be a beneficial therapeutic direction in cases of neuropsychiatric disorders involving NRXN1.
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | haploinsufficiency |
| disease | MESH | autism spectrum disorders |
| drug | DRUGBANK | Ketamine |