Abstract
Genetic and epigenetic changes in components of the Reelin-signaling pathway (RELN, DAB1) are associated with autism spectrum disorder (ASD) risk. Social communication deficits are a key component of the ASD diagnostic criteria, but the underlying neurogenetic mechanisms remain unknown. Reln insufficient mice exhibit ASD-like behavioral phenotypes including altered neonatal vocalization patterns. Reelin affects multiple pathways including through the receptors, Very low-density lipoprotein receptor (Vldlr), Apolipoprotein receptor 2 (Apoer2), and intracellular signaling molecule Disabled-1 (Dab1). As Vldlr was previously implicated in avian vocalization, here we investigate vocalizations of neonatal mice with a reduction or absence of these components of the Reelin-signaling pathway. Mice with low or no Dab1 expression exhibited reduced calling rates, altered call-type usage, and differential vocal development trajectories. Mice lacking Vldlr expression also had altered call repertoires, and this effect was exacerbated by deficiency in Apoer2. Together with previous findings, these observations 1) solidify a role for Reelin in vocal communication of multiple species, 2) point to the canonical Reelin-signaling pathway as critical for development of normal neonatal calling patterns in mice, and 3) suggest that mutants in this pathway could be used as murine models for Reelin-associated vocal deficits in humans.
Highlights
To further test that vocal deficits could be related to Very low-density lipoprotein receptor (Vldlr) insufficiency, we examined the effect of Vldlr deletion with or without Apoer[2]
Repertoire correlations of Vldlr−/−/ Apolipoprotein receptor 2 (Apoer2)−/− pups were significantly lower than those of Vldlr+/+/Apoer2+/+ pups (t-test p = 0.038). These findings indicate an association between highly similar repertoires within the groups of low or no Reelin-signaling pathway components, i.e. Dab[1], Vldlr, and Apoer[2]
In order to determine if Dab[1] or Vldlr insufficiency impacts patterns of early social communication, we characterized the age related calling patterns in Dab[1] and Vldlr/Apoer[2] deficient mice, generating novel findings
Summary
Reln+/− mice exhibit GAD67 down-regulation in the frontoparietal cortex[49], Purkinje cell loss and hypoplasia of the cerebellum[50] and parvalbumin-positive cell loss in the striatum[51], resulting in changes to cortico-striatal plasticity[50] These changes are parallel to those in human ASD cases which show the following abnormalities: low GAD67 across brain regions including the frontal cortex[52]; Purkinje cell loss and reduced cerebellar volume[53,54], and altered connectivity and function of the striatum[55,56]. Differences in repertoire based on genotype disappear as pups mature (P8-12) These findings indicate a deficit in early vocal communication in Reln+/− mice. These observations suggest that the Reelin-signaling pathway is essential for normal vocal development in multiple species
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