| First Author | Xu B | Year | 2023 |
| Journal | PLoS Genet | Volume | 19 |
| Issue | 2 | Pages | e1010659 |
| PubMed ID | 36848371 | Mgi Jnum | J:334083 |
| Mgi Id | MGI:7443673 | Doi | 10.1371/journal.pgen.1010659 |
| Citation | Xu B, et al. (2023) Allelic contribution of Nrxn1alpha to autism-relevant behavioral phenotypes in mice. PLoS Genet 19(2):e1010659 |
| abstractText | Copy number variations (CNVs) in the Neurexin 1 (NRXN1) gene, which encodes a presynaptic protein involved in neurotransmitter release, are some of the most frequently observed single-gene variants associated with autism spectrum disorder (ASD). To address the functional contribution of NRXN1 CNVs to behavioral phenotypes relevant to ASD, we carried out systematic behavioral phenotyping of an allelic series of Nrxn1 mouse models: one carrying promoter and exon 1 deletion abolishing Nrxn1alpha transcription, one carrying exon 9 deletion disrupting Nrxn1alpha protein translation, and one carrying an intronic deletion with no observable effect on Nrxn1alpha expression. We found that homozygous loss of Nrxn1alpha resulted in enhanced aggression in males, reduced affiliative social behaviors in females, and significantly altered circadian activities in both sexes. Heterozygous or homozygous loss of Nrxn1alpha affected the preference for social novelty in male mice, and notably, enhanced repetitive motor skills and motor coordination in both sexes. In contrast, mice bearing an intronic deletion of Nrxn1 did not display alterations in any of the behaviors assessed. These findings demonstrate the importance of Nrxn1alpha gene dosage in regulating social, circadian, and motor functions, and the variables of sex and genomic positioning of CNVs in the expression of autism-related phenotypes. Importantly, mice with heterozygous loss of Nrxn1, as found in numerous autistic individuals, show an elevated propensity to manifest autism-related phenotypes, supporting the use of models with this genomic architecture to study ASD etiology and assess additional genetic variants associated with autism. |
