Physiological and Pathological Role of mTOR Signaling in Astrocytes

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway is one of the key regulators of cellular energy metabolism. It senses diverse alterations in the extracellular environment such as availability of nutrients and growth factors, and mediates the corresponding intracellular response. In the brain, astrocytes crucially contribute to energy and neurotransmitter metabolism, and numerous other functions. However, the relevance of physiological, astrocytic mTOR signaling in maintaining brain homeostasis and function is not well understood. Pathophysiological mTOR signaling is involved in manifold diseases in the central nervous system and most of the knowledge about astrocytic mTOR signaling has been derived from observations on these disorders. Dysregulation of the mTOR signaling pathway impairs important functions of astrocytes including neurotransmitter uptake and -signaling as well as energy metabolism. Some of these alterations could trigger neuropathological conditions such as epilepsy. This review focuses on how mTOR signaling regulates properties of astrocytes, and how these signaling events might contribute to the physiological function of the brain.

Keywords: Astrocyte; Glutamate; Mitochondria; mTOR.

Fig. 1

The mTOR signaling pathway in astrocytes (simplified scheme). mTOR is activated by a signaling cascade which includes positive and negative regulators. Downstream of mTOR, important targets like 4EBP and the kinase S6K1 are activated. Black arrows indicate activation, while red T-shaped lines indicate inhibitory interactions. 4EBP - eIF4E Binding Protein, Akt - Protein kinase B, D-2-HG - D-2-Hydroxyglutarate, HABP2 - Hyaluronan-binding protein 2, IDH– Isocitrate dehydrogenase, InsR– Insulin receptor, mTORC1– mammalian target of rapamycin complex 1, Mut - mutation, PAR1 - Protease-activated receptor 1, PI3K - Phosphoinositide 3-kinase, PTEN - Phosphatase and tensin homolog, Rheb - Ras homolog enriched in brain, RTKs - Receptor tyrosine kinases, S6K1 - Ribosomal protein S6 kinase beta-1, TSC1/2 - Tuberous sclerosis complex 1 / 2. Created in BioRender. Hirrlinger, J. (2024) https://BioRender.com/a64w464

Fig. 2

Effects of activated mTOR signaling in astrocytes. Black arrows show alterations due to increased phosphorylation of S6K1 or which are reversible using rapamycin. Red dashed arrows show alterations in astrocytes derived from TSC tissue. Asterisks show changes in receptor composition due to activated mTOR signaling. AMPAR - α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Cx43 - connexin 43, EAAT - excitatory amino acid transporter, GLS– Glutaminase, GS - Glutamine synthetase, NMDAR - N-methyl-D-aspartate receptor. Created in BioRender. Hirrlinger, J. (2024) https://BioRender.com/z22t421