Mechanistic target of rapamycin signaling in human nervous system development and disease

Abstract

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates fundamental cellular processes including growth control, autophagy and metabolism. mTOR has key functions in nervous system development and mis-regulation of mTOR signaling causes aberrant neurodevelopment and neurological diseases, collectively called mTORopathies. In this mini review we discuss recent studies that have deepened our understanding of the key roles of the mTOR pathway in human nervous system development and disease. Recent advances in single-cell transcriptomics have been exploited to reveal specific roles for mTOR signaling in human cortical development that may have contributed to the evolutionary divergence from our primate ancestors. Cerebral organoid technology has been utilized to show that mTOR signaling is active in and regulates outer radial glial cells (RGCs), a population of neural stem cells that distinguish the human developing cortex. mTOR signaling has a well-established role in hamartoma syndromes such as tuberous sclerosis complex (TSC) and other mTORopathies. New ultra-sensitive techniques for identification of somatic mTOR pathway mutations have shed light on the neurodevelopmental origin and phenotypic heterogeneity seen in mTORopathy patients. These emerging studies suggest that mTOR signaling may facilitate developmental processes specific to human cortical development but also, when mis-regulated, cause cortical malformations and neurological disease.

Reversal of memory and autism-related phenotypes in Tsc2+/− mice via inhibition of Nlgn1

“…Moreover, mutations in genes related to mGluR signaling have been identified in individuals with ASD, further supporting a role for this pathway in the disorder ( Hadley et al, 2014 ). mTORC1 inhibition with rapamycin rescued several behavioral phenotypes in Tsc2 +/− mice ( Ehninger and Silva, 2011 ) and in other models of neurodevelopmental disorders ( Girodengo et al, 2022 ). Strikingly, we achieved rescue of TSC-related phenotypes in the Tsc2 +/− mice, without correcting hyperactivated mTORC1 ( Figure 4 ).…”

Control of circadian rhythm on cortical excitability and synaptic plasticity

“…mTOR is also implicated in the regulation of complex behaviors such as sleep, feeding and circadian rhythms ( Cao and Obrietan, 2010 ). The centrality of this pathway in the brain is underlined by the fact that mTOR dysregulations are implicated in cognitive deficits, defective synaptic plasticity and epilepsy ( Buffington et al, 2014 ; Borrie et al, 2017 ; Trovato et al, 2020 ; Nguyen and Bordey, 2021 ; Girodengo et al, 2022 ; Singla et al, 2022a ).…”

mTORC1 activity negatively regulates human hair follicle growth and pigmentation

“…TS is typically associated with hypopigmentation of skin (hypomelanotic macules; also referred to as “ash leaf spots”) and hair (poliosis), which is often used as an early diagnostic sign of TS (Cartron et al , 2021; Islam, 2021; Takahashi et al , 2022). Other manifestations of TS are the formation of various tumors and severe neurodevelopmental and renal abnormalities (Carmignac et al , 2021; Girodengo et al , 2022; Luo et al , 2022). Given the poliosis phenotype associated with TS, we hypothesized that mTORC1 activity may regulate human hair follicle (HF) pigmentation and hair graying (canities)—a complex, temporarily reversible, and stressor‐sensitive process that ultimately shuts off melanin production (melanogenesis) in the HF pigmentary unit (HFPU), typically long before it becomes irreversible due to a depletion of HF melanocyte stem cells (O'Sullivan et al , 2021; Rosenberg et al , 2021).…”