Exploring the pathogenic role of mTOR signaling in the 16p11.2 microdeletion

Chromosomal copy number variations (CNVs) are common genetic abnormalities in autism spectrum disorder (ASD) and have been identified in approximately 10 percent of individuals with ASD. Currently, there is a knowledge gap in the understanding of the molecular and synaptic mechanisms underlying CNV-associated ASD.

A microdeletion at human chromosome 16p11.2 is the most common ASD-linked CNV, and accounts for 0.5-1.0 percent of all ASD cases. The typical neurological abnormalities in individuals with 16p11.2 microdeletion are ASD, intellectual disability, language deficits, anxiety, attention deficit hyperactivity disorder and epilepsy. The high prevalence of disruptions in social, communication and behavioral domains among individuals carrying 16p11.2 microdeletions indicates that this region holds significant relevance for ASD and ASD-related phenotypes.

Di Tian and his colleagues recently characterized a mouse model of the 16p11.2 microdeletion (16p11.2df/+). These mice have altered mGluR5-dependent hippocampal plasticity and display several behavioral phenotypes associated with dysfunction of the hippocampus¹. Tian’s team will further assess this mouse model to gain additional mechanistic insights into the neurobiological consequences of the 16p11.2 microdeletion.

The PI3K-Akt-mTOR signaling pathway is commonly affected in neurodevelopmental disorders; however, its role in 16p11.2 microdeletion has not been explored. Tian and his team hypothesize that 16p11.2 microdeletion results in aberrant mTOR signaling, leading to abnormal morphological and behavioral phenotypes. To test this hypothesis, the team will modify the PI3K-Akt-mTOR pathway and assess morphological and behavioral outcomes. Results supporting this hypothesis could suggest that individuals with 16p11.2 microdeletion might benefit from treatments targeting mTOR signaling.

The long-term goal of this project is to provide new insights into ASD disease mechanisms and help inform new strategies for effective treatments.