The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model

Abstract

Circadian (~24 h) rhythms in physiology and behavior are evolutionarily conserved and found in almost all living organisms. The rhythms are endogenously driven by daily oscillatory activities of so-called “clock genes/proteins”, which are widely distributed throughout the mammalian brain. Mammalian (mechanistic) target of rapamycin (mTOR) signaling is a fundamental intracellular signal transduction cascade that controls important neuronal processes including neurodevelopment, synaptic plasticity, metabolism, and aging. Dysregulation of the mTOR pathway is associated with psychiatric disorders including autism spectrum disorders (ASD) and mood disorders (MD), in which patients often exhibit disrupted daily physiological rhythms and abnormal circadian gene expression in the brain. Recent work has found that the activities of mTOR signaling are temporally controlled by the circadian clock and exhibit robust circadian oscillations in multiple systems. In the meantime, mTOR signaling regulates fundamental properties of the central and peripheral circadian clocks, including period length, entrainment, and synchronization. Whereas the underlying mechanisms remain to be fully elucidated, increasing clinical and preclinical evidence support significant crosstalk between mTOR signaling, the circadian clock, and psychiatric disorders. Here, we review recent progress in understanding the trilateral interactions and propose an “interaction triangle” model between mTOR signaling, the circadian clock, and psychiatric disorders (focusing on ASD and MD).

Skeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent

“…Thus, a proper functioning of the circadian clock is critical to maintain homeostasis and physiological functions, and the perturbation of this system may result in severe pathologies including cancer 41,42 . Abnormal changes in circadian rhythms have been reported in jet lag 43 , night-shift workers 44 , cancer 45,46 , metabolic disorders 47,48 , mental disorders 49,50 , and also as a consequence of spaceflight [51][52][53] . Space travellers report circadian rhythm disruption during spaceflight, which is visible in many physiological aspects, for example shorter sleep durations 54 .…”

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 ).…”

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process

“…Conversely, the downregulated GPR19 data cohorts were more strongly associated with ‘Interleukin signaling’, ‘mTOR signaling’, ‘IGF-1 signaling’ and ‘Nuclear Laminopathies’. All of these diverse functions strongly converge with respect to the pathomechanisms linked to pathological aging (DNA damage—[ 73 ]; Cholesterol regulation [ 188 , 189 , 190 ]; stem cell management [ 191 , 192 ]; UPR [ 193 , 194 ]; mTOR signaling [ 195 , 196 ]; IGF-1 signaling [ 197 , 198 ]; laminopathies [ 199 , 200 ]).…”