Nikolaeva, Ina. Targeting the PI3K/Akt/mTOR pathway in traumatic brain injury and developmental disease. Retrieved from https://doi.org/doi:10.7282/T3CZ39BH
DescriptionThe PI3K/Akt/mTOR signaling pathway mediates many aspects of cell growth and regeneration. Dysregulation of the pathway during development or following injury can lead to severe symptoms, including behavioral disorders, intellectual disability and seizures. We investigated the effects of excess PI3K/Akt/mTOR signaling in the mouse brain during embryonic development and following traumatic brain injury; we then tested out known inhibitors of the pathway for their potential to prevent or reverse the resulting damage. Here, we described the time course and cell specificity of mTORC1 signal activation in the mouse hippocampus after moderate controlled cortical impact (CCI), and identified an early neuronal peak of activity that occurs within few hours after injury. We suppressed this peak activity by a single injection of the mTORC1 inhibitor rapamycin one hour after CCI, and showed that this acute treatment significantly diminishes the extent of neuronal death and astrogliosis within 24 hours after injury. We investigated two other suppressor compounds of the pathway, mTORC1 inhibitor RAD001 and Akt inhibitor MK-2206, in an in vitro mouse model of excess developmental PI3K/Akt/mTOR activity; increased signaling in this pathway is associated with multiple brain overgrowth disorders in humans. We used excitatory neuron-specific gene deletion of the PI3K antagonist Pten as a method for disinhibiting the pathway. We established Pten-mutant forebrain neuronal cultures as an in vitro model of brain overgrowth that may facilitate the identification of pharmacological treatments. We found that Pten-mutant neurons exhibit dramatic cellular hypertrophy, including increased soma size and dendrite complexity, which can be reversed partially with mTORC1 inhibitor RAD001 and fully with Akt inhibitor MK-2206. Our findings suggest that acute Akt and mTORC1 inhibition may offer viable therapeutic approaches for preventing or reversing pathologies caused by excess PI3K/Akt/mTOR signaling, both in the developing and healing brain.