Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex

Abstract

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.

Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2

“…We have previously shown that Cre-dependent deletion of Rictor reduces p-473 Akt levels in cultured hippocampal neurons, indicative of suppressed mTORC2 activity ( Karalis et al, 2021b ). Due to technical limitations of the antibody, we were not able to assess p-473 at the level of individual neurons in brain sections.…”

“…In mature neurons, mTOR controls neuronal morphology, physiology, and synaptic properties ( Costa-Mattioli and Monteggia, 2013 ; Hoeffer and Klann, 2010 ; Switon et al, 2017 ). Consequently, dysregulation of mTOR signaling has a profound impact on nervous system function and several neurodevelopmental, psychiatric and neurodegenerative disorders are directly caused by or associated with altered mTOR activity ( Costa-Mattioli and Monteggia, 2013 ; Karalis et al, 2021b ; Lipton and Sahin, 2014 ).…”

“…Manipulations used to study mTOR signaling are often not specific to one complex. Rapamycin treatment can interfere with both mTORC1 and mTORC2 signaling ( Karalis and Bateup, 2021a ; Sarbassov et al, 2006 ), deletion of Pten activates both mTORC1 and mTORC2 ( Chen et al, 2019 ), and loss of Tsc1 activates mTORC1 but suppresses mTORC2 signaling ( Carson et al, 2012 ; Karalis et al, 2021b ; Meikle et al, 2008 ). Consequently, from the current literature it is difficult to disentangle which mTOR complex is responsible for the observed effects.…”