Deletion of Pten in Oxytocinergic Cells Leads to Social Behavioral Deficits and Decreased Oxytocinergic Cell Number

Background:  Mutations in Phosphatase and tensin homolog (PTEN), which encodes a negative regulator of the PI3K-Akt-mTOR pathway, are more common in the subset of ASD patients who show macrocephaly (enlarged head circumference). We have previously shown that a mouse model of Pten germline haploinsufficiency (Pten^+/-) exhibits ASD-relevant behavioral deficits, with social impairment in both sexes, and male repetitive behavior, mood and anxiety phenotypes.  These deficits are consistent with those seen in oxytocin (Oxt) or oxytocin receptor (Oxtr) knockout mice, suggesting that Pten^+/- may affect behavior through this system.  Oxytocin has been shown to mediate social behavior, mood, and anxiety, and Oxt neurons project to brain areas relevant to social behavior and ASD. Further, OXTR is an ASD risk factor, and individuals with ASD have shown decreased levels of circulating Oxt.  We have also found that Pten^+/- mice have less Oxt immunoreactivity and plasma Oxt than Pten^+/+ littermates.

Objectives:  We planned to assess whether Pten plays a cell autonomous role in behavior by altering the developmental trajectory of Oxt neurons, leading to dysregulation of behaviors relevant to ASD and comorbid disorders.  We predict that hyperactive mTOR signaling, as caused by Pten mutations, leads to increased apoptosis in Oxt neurons and subsequent deficits in behavior relevant to ASD and comorbid disorders (e.g., mood, anxiety). 

Methods:  We tested male and female mice with Pten haploinsufficiency (Oxt-Cre^+/-; Pten^loxP/+) or deletion (Oxt-Cre^+/-; Pten^loxP/loxP) in Oxt neurons, and Oxt-Cre^-/- controls, on ASD-relevant behaviors (social behavior: social approach, social recognition; repetitive, stereotyped behavior: marble burying) and assays related to ASD comorbidities (mood disorders: tail suspension test; anxiety disorders: dark-light emergence, open field test).  We are also characterizing Oxt neurons in the paraventricular nucleus of the hypothalamus and the supraoptic nucleus using immunohistochemistry during development and in adulthood.

Results:  We found that Oxt-Cre^+/-; Pten^loxP/loxP mice showed deficits in social behavior, with females failing to prefer a social stimulus, and males showing a decreased preference for the social stimulus, as well as decreased dishabituation in the habituation/dishabituation test of social recognition.  Male Oxt-Cre^+/-; Pten^loxP/loxP mice showed decreased anxiety on the open field and increased depression-like behavior.  Thus, Oxt-Cre^+/-; Pten^loxP/loxP mice appear to recapitulate many of the behavioral phenotypes observed in Pten^+/- mice.  Histological analyses are currently underway to determine the neuroanatomical consequences of this mutation and how it may induce the observed behavioral abnormalities.

Conclusions:  The observation of similar phenotypes in Oxt-Cre^+/-; Pten^loxP/loxP and Pten^+/- mice suggests that decreased Pten in Oxt neurons is a contributing factor in the social, mood, and anxiety behavioral phenotypes shown in Pten-deficient mice.