Abstract
The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding α-neurexin I (Nrxn1α) and α-neurexin II (Nrxn2α), in individuals with autism spectrum disorders and schizophrenia. However, the link between α-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 Nrxn1α or Nrxn2α. We found that in a test of social approach, Nrxn1α HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1α HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2α HET mice. Nrxn2α HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1α and Nrxn2α 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 α-neurexin I and α-neurexin II in mice leads to phenotypes relevant to autism and schizophrenia.
Highlights
The neurexins are a family of presynaptic cell adhesion molecules
We found that Nrxn2␣ homozygous KO mice display a deficit in social responses—a core symptom of autism—as well as behaviors related to anxiety (Dachtler et al, 2014), which is often comorbid with autism (White, Oswald, Ollendick, & Scahill, 2009)
Nrxn2␣ HET mice showed no preference for exploring the novel object (Figure 2a; one-way analysis of variance (ANOVA), F(2, 62) ϭ 7.74, p ϭ .001, pairwise comparison reveals a significant difference between WT and Nrxn2␣ HET mice [p ϭ .0007] but not between WT and Nrxn1␣ HET mice [p ϭ .34]), despite all genotypes spending similar amounts of time exploring the objects during the training and test phases (Supplemental Material Figure 2a– b)
Summary
The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding ␣-neurexin I (Nrxn1␣) and ␣-neurexin II (Nrxn2␣), in individuals with autism spectrum disorders and schizophrenia. 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␣ or Nrxn2␣. We used homozygous Nrxn2␣ knockout (KO) mice to assess the hypothesis that behavioral phenotypes related to autism could be associated with ␣-neurexin II deficiency. Nrxn1␣ homozygous KO mice display heightened aggression toward, and less social investigation of, juvenile mice, while expressing anxiety-like behavior in a light/dark box (Grayton, Missler, Collier, & Fernandes, 2013) These mice have reduced prepulse inhibition (Etherton, Blaiss, Powell, & Sudhof, 2009), a measure of sensorimotor gating, which is altered in schizophrenic and some autistic patients (Braff, Grillon, & Geyer, 1992; Perry, Minassian, Lopez, Maron, & Lincoln, 2007). We assessed behavioral performance of Nrxn1␣ HET and Nrxn2␣ HET mice in a range of behavioral tests for phenotypes relevant to the human disorders
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