Pten Haploinsufficient Mice Show Selective Impairments in Autism-Relevant Behavioral Tests

Friday, May 16, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
A. E. Clipperton-Allen1 and D. T. Page2, (1)Neuroscience, The Scripps Research Institute, Jupiter, FL, (2)Department of Neuroscience, The Scripps Research Institute, Jupiter, FL
Background:  Phosphatase and tensin homolog (PTEN) is one of several genes encoding negative regulators of the PI3K-Akt-mTOR pathway that have been identified as autism spectrum disorder (ASD) risk factors.  Mutations in PTEN have been reported in individuals with ASD and macrocephaly. Using a mouse model of Pten germline haploinsufficiency (Pten+/-), we previously found that mutant mice show both deficits in social approach behavior and brain overgrowth.  

Objectives:  The distribution of Pten mRNA in the brain is broad, as is the brain overgrowth in Pten+/- mice.  However, it is not known if this translates into broad effects on behavior in these mice, or if effects are restricted to specific domains or vulnerable neural systems. Our aim is to fill in this gap in our knowledge.

Methods:  We tested male and female Pten+/- mice on ASD-relevant behaviors (social behavior: social approach, social novelty, social recognition; repetitive, stereotyped behavior: marble burying), as well as assays related to ASD comorbidities (mood disorders: tail suspension test, forced swim test; anxiety disorders: dark-light emergence, open field test; emotional learning and memory: trace fear conditioning; sleep disorders: circadian rhythm and activity) and relevant control measures (hotplate, rotarod).

Results:  Pten+/- mice showed decreased social approach and social novelty, and impaired social recognition as assessed by habituation/dishabituation, as well as brain overgrowth.  Male Pten+/- mice buried more marbles (suggesting an increase in repetitive behavior), showed increased immobility in tail suspension and forced swim tests (indicating increased depression-like behavior), and increased center and light chamber time in the open field and dark-light emergence tests, respectively (indicating decreased anxiety-like behavior). We also found that Pten+/- females exhibited abnormalities in circadian rhythm and activity and emotional learning.  Our results suggest that Pten may function in dopamine (DA) neurons to affect behavior; thus, we tested mice in which Pten has been inactivated in DA neurons via the Cre-loxP system (DAT-Pten-cKO) on social behavior assays. Results from this experiment indicate that DAT-Pten-cKO mice may also show impairments in social behavior.

Conclusions:  We found that the behavioral phenotypes present in Pten+/- mice are selective, despite the broad distribution of Pten mRNA and overgrowth in the brain.  This suggests that specific neural systems are vulnerable to disruption by Pten mutations.  One possible system through which this disruption may be affecting behavior is the DA system; our results indicate that conditional inactivation of Pten in neurons of this system may lead to social behavioral deficits.  Ongoing studies are exploring the involvement of dopaminergic neurons and other cell types in behavioral deficits resulting from mutation of Pten.

See more of: Animal Models
See more of: Animal Models