mTOR pathway disruption in GABAergic neurons impacts morphological and functional development of cortical and thalamic somatosensory areas in a mouse model of autism spectrum disorder

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1/2 genes, leading to mTOR pathway dysregulation and diverse cellular impacts. Individuals with TSC face severely heightened risk of autism spectrum disorder (ASD), highlighting a genetic link between the two conditions. To model ASD etiology in the context of TSC, we developed a new mouse model with Tsc2 knockout induced mid-gestation in all postmitotic, GABAergic neurons. As ASD and TSC both involve somatosensory processing challenges, we utilized our mouse model to assess how the mutation affects the cortical and thalamic somatosensory processing areas. Our analyses shown increase in the number of myelinated axons in all studied regions, as well as changed electrophysiology of their neurons. RNA-seq profiling uncovered mutation-induced, differential gene expression changes in somatosensory cortex, thalamus and thalamic reticular nucleus. Furthermore, mutant mice displayed deficits in social interaction and heightened sensitivity to tactile stimuli. Our study underscores the role of mTOR dysregulation in GABAergic neurons in shaping somatosensory development and ASD-like phenotypes in a novel mouse model of TSC. By elucidating the molecular and functional alterations in primary somatosensory regions, we contribute to understanding the pathophysiology of ASD and inform potential therapeutic targets for individuals with TSC-associated ASD.