Deletion of PTEN produces deficits in conditioned fear and increases fragile X mental retardation protein.

The phosphatase and tensin homolog detected on chromosome 10 (PTEN) gene product modulates activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The PI3K pathway has been found to be involved in the regulation of the fragile X mental retardation protein, which is important for long-term depression and in the formation of new memories. We used delayed fear conditioning and trace fear conditioning to determine learning and memory deficits in neuron subset-specific Pten (NS-Pten) conditional knockout (KO) mice. We found that NS-Pten KO mice had deficits in contextual learning and trace conditioning, but did not have deficits in the ability to learn a conditioned stimulus. Furthermore, we found increased levels in the total and phosphorylated forms of the fragile X mental retardation protein (FMRP) in the hippocampus of NS-Pten KO mice.

Neuronal subset-specific deletion of Pten results in aberrant Wnt signaling and memory impairments.

The canonical Wnt and PI3K/Akt/mTOR pathways both play critical roles in brain development early in life. There is extensive evidence of how each pathway is involved in neuronal and synaptic maturation, however, how these molecular networks interact requires further investigation. The present study examines the effect of neuronal subset-specific deletion of phosphatase and tensin homolog (Pten) in mice on Wnt signaling protein levels and associated cognitive impairments. PTEN functions as a negative regulator of the PI3K/Akt/mTOR pathway, and mutations in Pten can result in cognitive and behavioral impairments. We found that deletion of Pten resulted in elevated Dvl2, Wnt5a/b, and Naked2, along with decreased GSK3ß hippocampal synaptosome protein expression compared to wild type mice. Aberrations in the canonical Wnt pathway were associated with learning and memory deficits in Pten knockout mice, specifically in novel object recognition and the Lashley maze. This study demonstrates that deletion of Pten not only significantly impacts PI3K/Akt/mTOR signaling, but affects proper functioning of the Wnt signaling pathway. Overall, these findings will help elucidate how the PI3K/Akt/mTOR pathway intersects with Wnt signaling to result in cognitive impairments, specifically in memory.

Superimposing Status Epilepticus on Neuron Subset-Specific PTEN Haploinsufficient and Wild Type Mice Results in Long-term Changes in Behavior.

We evaluated the effects of superimposing seizures on a genetic mutation with known involvement in both Autism Spectrum Disorder and in epilepsy. Neuron-subset specific (NS)-Pten heterozygous (HT) and wildtype (WT) adult mice received either intraperitoneal injections of kainic acid (20 mg/kg) to induce status epilepticus or the vehicle (saline). Animals then received a battery of behavioral tasks in order to evaluate activity levels, anxiety, repetitive-stereotyped behavior, social behavior, learning and memory. In the open field task, we found that HT mice after seizures showed a significant increase in total activity and total distance in the surround region of the open field. In the elevated plus maze task, we found that HT mice after seizures displayed increased total distance and velocity as compared to HT mice that did not undergo seizures and WT controls. In the social chamber test, we found the HT mice after seizures displayed an impairment in social behavior. These findings demonstrate that superimposing seizures on a genetic mutation can result in long-term alterations in activity and social behavior in mice.

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

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.