Heterozygous Deletion of α-Neurexin I or α-Neurexin II Results in Behaviors Relevant to Autism and Schizophrenia

The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding alpha-neurexin I (Nrxn1 alpha) and alpha-neurexin II (Nrxn2 alpha), in individuals with autism spectrum disorders and schizophrenia. However, the link between alpha-neurexin deficiency and the manifestation of psychiatric disorders remain unclear. To assess whether the heterozygous loss of neurexins results in behaviors relevant to autism or schizophrenia, we used mice with heterozygous (HET) deletion of Nrxn1 alpha or Nrxn2 alpha. We found that in a test of social approach, Nrxn1 alpha HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1 alpha HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2 alpha HET mice. Nrxn2 alpha HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1 alpha and Nrxn2 alpha genotypic effects were specific, as neither HET deletion had effects on a wide range of other behavioral measures, including several measures of anxiety. Our findings demonstrate that the heterozygous loss of alpha-neurexin I and alpha-neurexin II in mice leads to phenotypes relevant to autism and schizophrenia.