Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins

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.

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

“…Both increased anxiety and lack of appropriate fear are reported in human ASD, and this range of behaviors is also seen in models of neuronal Pten loss. The Gfap-Cre; Pten loxP/loxP model exhibits lower than usual anxiety levels in combination with hyperactivity, while the Nse-cre; Pten loxP/loxP mouse showed high levels of anxiety-like behavior, as well as increased locomotion in the open field test [62,87]. The Pten m3m4 model also demonstrated poor balance on the accelerating rotarod task, potentially in keeping with the motor clumsiness reported in individuals with high-functioning ASD [61,89].…”

“…Compared with wild-type mice, the first model to demonstrate reduced social behavior was the Nse-cre; Pten loxP/loxP mouse, which showed a reduced preference for another mouse than a nonsocial object [62]. This decrease in social behavior was replicated in later models based on Pten loss in more restricted populations, such as granule cells of the dentate gyrus and cerebellum or neural progenitors in adult animals [67,87]. Having established the critical role of neuronal Pten activity for normal social behavior, other models add context for what may occur in PHTS where PTEN mutations are germline and behavioral phenotypes are the collective expression of this pathology in every cell type.…”

“…In addition to social behavior deficits, several mouse models of Pten loss exhibit behaviors relevant to other core symptoms of ASD or frequent comorbidities. Repetitive behaviors, now a critical half of ASD diagnosis, are seen in Gfap-Cre; Pten loxP/loxP and male Pten +/-animals as repetitive marble burying or selfgrooming [84,87]. Although epilepsy is not part of Cre-lox = Cre-loxP-mediated recombination; NA = not applicable the diagnostic criteria for ASD, its association with germline PTEN mutations in several recent case reports adds new relevance to the seizure phenotypes observed in multiple mouse models of neural Pten loss [30-33, 62, 86].…”

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

“…Recent studies have shown that mTOR signaling is linked to ASD (Tsai et al, 2012) (Lugo et al, 2014) (Garg et al, 2013). Dysregulation of upstream mTOR signaling leads to ASD.…”

Autism and Epilepsy: Exploring the Relationship Using Experimental Models

“…Behavioral tests discussed above can be readily applied to autism models as well. Mice with a deletion of PTEN (a gene involved in the regulation of the mTOR pathway) had deficits in SP, SC, and marble burying (56). Mice with BTBR mutations express autistic features (on SC test) but are not seizure-prone.…”