Strategy Could Help Treat Behavioral Abnormalities Linked to Autism

Researchers report in Nature Medicine a potential new treatment strategy for autism spectrum disorder – for which many cases are linked to mutated PTEN. Now, using Pten-deficient mice, researchers discover that a previously unexplored pathway goes “awry” in the brain, and by “rescuing” this pathway, it is possible to reverse behavioral and neurophysiological abnormalities.

Autism spectrum disorder

Autism spectrum disorder (ASD), commonly referred to as “autism”, is a developmental disorder that affects approximately 1 in 59 children in the U.S. The disorder is roughly four times more common in males compared to females and is linked to difficulties with social communication and interaction as well as repetitive behaviors.

PTEN and autism

Autistic children with mutations in PTEN typically develop macrocephaly, intellectual disability and suffer with epilepsy. Currently there are no approved treatments for the condition. Researchers now report that they have developed a novel therapeutic approach, using a mouse model, that could potentially treat autism symptoms related to mutated PTEN.

"PTEN is associated with the mTOR signaling pathway, which includes two distinct molecular complexes – mTORC1 and mTORC2 – each one regulating different cellular functions," explains Chien-Ju Chen, first author of the study, in a recent press release.

“Normal” PTEN is a negative regulator of mTOR signaling; however, in individuals with mutated PTEN this signaling can become dysregulated. Rapamycin-mediated inhibition of mTORC1 activity has been previously shown to improve behavioral and neurophysiological abnormalities in Pten-deficient mice. Therefore, it was believed that the neurological symptoms associated with mutated PTEN and other mTORopathies were due to hyperactivation of mTORC1-mediated protein synthesis.

However, the authors note that mTORC2 activity is also upregulated in the brain of patients with PTEN-deficiency and in Pten-deficient mice.

Study design

To investigate the involvement of mTORC1 or mTORC2 in the neural pathophysiology linked to the loss of PTEN, the team utilized molecular genetic approaches to suppress mTORC1 and mTORC2.

"The results were quite surprising because they went against the traditional view of the field," says Costa-Mattioli, corresponding study author, in a recent press release.

Chen, et al. discovered that by genetically silencing the mTORC1 complex in Pten-deficient mice, brain size was restored – but it didn’t alter survival, behavioral symptoms or the number seizures.

However, there were some unexpected findings…

“Unexpectedly, genetically silencing mTORC2 complex activity resulted in prolonged lifespan, suppressed seizures, rescue of long-term memory and reduced autism spectrum disorder-like behaviors," explains Costa-Mattioli.

Homing in on mTORC2

Taking a more therapeutically oriented approach, the team developed an antisense oligonucleotide (ASO) that could inhibit mTORC2 activity. The ASO works by specifically targeting one of mTORC2’s key components “Rictor”.

"Amazingly, when we administered a single injection of the antisense oligonucleotide, we were able to reverse the abnormal behaviors and reduce seizures in Pten-deficient mice," Chen says.

Until now, efforts have been directed towards developing therapeutics that target mTORC1 rather than mTORC2.

Now, with a clearer understanding of the link between mTORC2 and behavioral and neurological changes in Pten-deficient mice, should we be shifting attention towards ways to modulate mTORC2 activity?

"For other conditions, like spinal muscular atrophy, antisense oligonucleotides have successfully been translated into the clinic. This opens the possibility that either this or drug-based therapeutic modulation of mTORC2 activity also could be developed into a promising strategy to treat neurological disorders in which mTORC2 activity is dysregulated," concludes Costa-Mattioli.

Reference: Chen, et al. (2019) Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency. Nature Medicine. DOI: https://doi.org/10.1038/s41591-019-0608-y