Abstract
Many genes have been implicated in the underlying cause of autism but each gene accounts for only a small fraction of those diagnosed with autism. There is increasing evidence that activity-dependent changes in neuronal signaling could act as a convergent mechanism for many of the changes in synaptic proteins. One candidate signaling pathway that may have a critical role in autism is the PI3K/AKT/mTOR pathway. A major regulator of this pathway is the negative repressor phosphatase and tensin homolog (PTEN). In the current study we examined the behavioral and molecular consequences in mice with neuron subset-specific deletion of PTEN. The knockout (KO) mice showed deficits in social chamber and social partition test. KO mice demonstrated alterations in repetitive behavior, as measured in the marble burying test and hole-board test. They showed no changes in ultrasonic vocalizations emitted on postnatal day 10 or 12 compared to wildtype (WT) mice. They exhibited less anxiety in the elevated-plus maze test and were more active in the open field test compared to WT mice. In addition to the behavioral alterations, KO mice had elevation of phosphorylated AKT, phosphorylated S6, and an increase in S6K. KO mice had a decrease in mGluR but an increase in total and phosphorylated fragile X mental retardation protein. The disruptions in intracellular signaling may be why the KO mice had a decrease in the dendritic potassium channel Kv4.2 and a decrease in the synaptic scaffolding proteins PSD-95 and SAP102. These findings demonstrate that deletion of PTEN results in long-term alterations in social behavior, repetitive behavior, activity, and anxiety. In addition, deletion of PTEN significantly alters mGluR signaling and many synaptic proteins in the hippocampus. Our data demonstrates that deletion of PTEN can result in many of the behavioral features of autism and may provide insights into the regulation of intracellular signaling on synaptic proteins.
Highlights
In the last few years the rate of children with autism spectrum disorders (ASDs) has risen from a prevalence rate of 0.6 % in 2000 to the current rate of 1 in 88, as reported by the Centers for Disease Control and Prevention (CDC; 2012)
We found a significant impairment in the social partition test in NSPten KO mice
In phase B where a mouse was placed in a cup in one of the chambers and a novel object was placed in the cup in the other chamber there was evidence of social behavior deficits in the NS-Pten KO mice
Summary
In the last few years the rate of children with autism spectrum disorders (ASDs) has risen from a prevalence rate of 0.6 % in 2000 to the current rate of 1 in 88, as reported by the Centers for Disease Control and Prevention (CDC; 2012). Many of the genes implicated in ASDs encode synaptic proteins such as the scaffolding proteins Shank 3, Homer, and PSD-95, and the synaptic adhesion molecules neuroligin and neuroexin (Delorme et al, 2013) Many of these gene mutations are rare and only account for a small fraction of the cases of ASDs. many of these gene mutations are rare and only account for a small fraction of the cases of ASDs Another approach to understanding the molecular mechanisms underlying ASDs has been to examine single gene mutations that share a high comorbidity with ASD such as fragile X syndrome, Tuberous sclerosis complex, Timothy Syndrome, Rett Syndrome, and Angelmen syndrome (Matsuura et al, 1997; Baker et al, 1998; Amir et al, 1999; Splawski et al, 2004; Hatton et al, 2006). There is a growing consensus that gene mutations associated with the regulation of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) intracellular signaling pathway play a significant role in mediating the behavioral abnormalities that characterize autism
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