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Heterozygous deletion of ?-neurexin I or ?-neurexin II results in behaviors relevant to autism and schizophrenia.

ABSTRACT: 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. However, the link between ?-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? or Nrxn2?. We found that in a test of social approach, Nrxn1? HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1? HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2? HET mice. Nrxn2? HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1? and Nrxn2? 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 ?-neurexin I and ?-neurexin II in mice leads to phenotypes relevant to autism and schizophrenia.

SUBMITTER: Dachtler J

PROVIDER: S-EPMC4655861 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia.

Dachtler James J Ivorra Jose L JL Rowland Tessa E TE Lever Colin C Rodgers R John RJ Clapcote Steven J SJ

Behavioral neuroscience 20151201 6

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 u ...[more]

PMID: 26595880

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Project description:Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms such as low heart rate variability and cardiovascular complications in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder's pathophysiology as well. The present study explored this hypothesis using a model of subdiaphragmatic vagal deafferentation (SDA) in male rats. SDA represents the most complete and selective vagal deafferentation method existing to date as it leads to complete disconnection of all abdominal vagal afferents while sparing half of the abdominal vagal efferents. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which manifests itself as increased sensitivity to acute amphetamine treatment and elevated accumbal levels of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that the brain transcriptome, dopamine neurochemistry, and behavioral functions implicated in schizophrenia are subject to visceral modulation through abdominal vagal afferents. Our findings may encourage the further establishment and use of therapies for schizophrenia that are based on vagal interventions.SIGNIFICANCE STATEMENT The present work provides a better understanding of how disrupted vagal afferent signaling can contribute to schizophrenia-related brain and behavioral abnormalities. More specifically, it shows that subdiaphragmatic vagal deafferentation (SDA) in rats leads to (1) brain transcriptional changes in functional networks related to schizophrenia, (2) increased sensitivity to dopamine-stimulating drugs and elevated dopamine levels in the nucleus accumbens, and (3) impairments in sensorimotor gating and the attentional control of associative learning. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions.

Dataset Information

Heterozygous deletion of ?-neurexin I or ?-neurexin II results in behaviors relevant to autism and schizophrenia.

Publications

Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia.

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