Genetic Suppression of mTOR Rescues Synaptic and Social Behavioral Abnormalities in a Mouse Model of Pten Haploinsufficiency.

Abstract

Heterozygous mutations in PTEN, which encodes a negative regulator of the mTOR and β-catenin signaling pathways, cause macrocephaly/autism syndrome. However, the neurobiological substrates of the core symptoms of this syndrome are poorly understood. Here, we investigate the relationship between cerebral cortical overgrowth and social behavior deficits in conditional Pten heterozygous female mice (Pten cHet) using Emx1-Cre, which is expressed in cortical pyramidal neurons and a subset of glia. We found that conditional heterozygous mutation of Ctnnb1 (encoding β-catenin) suppresses Pten cHet cortical overgrowth, but not social behavioral deficits, whereas conditional heterozygous mutation of Mtor suppresses social behavioral deficits, but not cortical overgrowth. Neuronal activity in response to social cues and excitatory synapse markers are elevated in the medial prefrontal cortex (mPFC) of Pten cHet mice, and heterozygous mutation in Mtor, but not Ctnnb1, rescues these phenotypes. These findings indicate that macroscale cerebral cortical overgrowth and social behavioral phenotypes caused by Pten haploinsufficiency can be dissociated based on responsiveness to genetic suppression of Ctnnb1 or Mtor. Furthermore, neuronal connectivity appears to be one potential substrate for mTOR-mediated suppression of social behavioral deficits in Pten haploinsufficient mice. Autism Res 2019, 12: 1463-1471. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A subgroup of individuals with autism display overgrowth of the head and the brain during development. Using a mouse model of an autism risk gene, Pten, that displays both brain overgrowth and social behavioral deficits, we show here that that these two symptoms can be dissociated. Reversal of social behavioral deficits in this model is associated with rescue of abnormal synaptic markers and neuronal activity.