Control of circadian rhythm on cortical excitability and synaptic plasticity

Abstract

Living organisms navigate through a cyclic world: activity, feeding, social interactions are all organized along the periodic succession of night and day. At the cellular level, periodic activity is controlled by the molecular machinery driving the circadian regulation of cellular homeostasis. This mechanism adapts cell function to the external environment and its crucial importance is underlined by its robustness and redundancy. The cell autonomous clock regulates cell function by the circadian modulation of mTOR, a master controller of protein synthesis. Importantly, mTOR integrates the circadian modulation with synaptic activity and extracellular signals through a complex signaling network that includes the RAS-ERK pathway. The relationship between mTOR and the circadian clock is bidirectional, since mTOR can feedback on the cellular clock to shift the cycle to maintain the alignment with the environmental conditions. The mTOR and ERK pathways are crucial determinants of synaptic plasticity and function and thus it is not surprising that alterations of the circadian clock cause defective responses to environmental challenges, as witnessed by the bi-directional relationship between brain disorders and impaired circadian regulation. In physiological conditions, the feedback between the intrinsic clock and the mTOR pathway suggests that also synaptic plasticity should undergo circadian regulation.

Keywords: LTP; chloride homeostasis; circadian rhythm; mTOR; memory and learning; neuronal excitability.

FIGURE 1

Stages of the autonomous circadian clock. (A) The cycle begins with the dimerization of CLOCK and BMAL1 in the cytosol and the following translocation to the nucleus. (B) The CLOCK:BMAL1 heterodimers bind to E-box response elements to promote the expression of several genes including Cry and Per. Cytosolic PER takes part in a regulatory loop with mTOR by activating TSC1, and upstream inhibitor of mTOR thus contributing to the entrainment of mTOR to the circadian cycle (Wu et al., 2019). PER activity is curtailed by its degradation mediated by CK1. (C) The CRY:PER heterodimers translocate in the nucleus and inhibit the association of CLOCK:BMAL1 with the DNA thus repressing gene expression. (D) BMAL1 shuttles between the nucleus and the cytoplasm where it is phosphorylated by S6K and then participates to the rhythmic activation of translation (Lipton et al., 2015). Orange boxes indicate the activator elements of the translation feedback, while elements in green and magenta indicate the repressors. Filled arrowheads indicate protein translocations and positive interactions. Lines terminating with a circle indicate inhibitory interactions.

FIGURE 2

(A) Relative time course of the processes controlling time keeping in the SCN. ZT stands for Zeitgeber Time with 0 at dawn. Exposure to blue light at the end of darkness causes an increase of neuronal activity in the SCN and phosphorylation of ERK. The activation of the ERK pathway is followed by the activation of gene expression mediated by CREB and the activation of mTOR leading to protein synthesis. Phosphorilated S6 kinase (pS6K) is a proxy for mTORC1 activation. The temporal flow of the autonomous circadian clock is reported by the expressions of BMAL1 and PER that have a phase difference of about 12 h. (B) Light delivered during the late night increases firing in the SCN thus anticipating ERK phosphorylation, mTOR activation and protein synthesis. In this way, BMAL1 expression is anticipated thus leading to an overall anticipation of the circadian loop. (C) mTOR is the converging point between the environmental stimuli and the autonomous circadian clock.