Self-reinforcing effects of mTOR hyperactive neurons on dendritic growth

Loss of the mTOR pathway negative regulator PTEN from hippocampal dentate granule cells leads to neuronal hypertrophy, increased dendritic branching and aberrant basal dendrite formation in animal models. Similar changes are evident in humans with mTOR pathway mutations. These genetic conditions are associated with autism, cognitive dysfunction and epilepsy. Interestingly, humans with mTOR pathway mutations often present with mosaic disruptions of gene function, producing lesions that range from focal cortical dysplasia to hemimegalanecephaly. Whether mTOR-mediated neuronal dysmorphogenesis is impacted by the number of affected cells, however, is not known. mTOR mutations can produce secondary comorbidities, including brain hypertrophy and seizures, which could exacerbate dysmorphogenesis among mutant cells. To determine whether the percentage or “load” of PTEN knockout granule cells impacts the morphological development of these same cells, we generated two groups of PTEN knockout mice. In the first, PTEN deletion rates were held constant, at about 5%, and knockout cell growth over time was assessed. Knockout cells exhibited significant dendritic growth between 7 and 18 weeks, demonstrating that aberrant dendritic growth continues even after the cells reach maturity. In the second group of mice, PTEN was deleted from 2 to 37% of granule cells to determine whether deletion rate was a factor in driving this continued growth. Multivariate analysis revealed that both age and knockout cell load contributed to knockout cell dendritic growth. Although the mechanism remains to be determined, these findings demonstrate that large numbers of mutant neurons can produce self-reinforcing effects on their own growth.