mTOR in Brain Physiology and Pathologies

Abstract

TOR (target of rapamycin) and its mammalian ortholog mTOR have been discovered in an effort to understand the mechanisms of action of the immunosuppressant drug rapamycin extracted from a bacterium of the Easter Island (Rapa Nui) soil. mTOR is a serine/threonine kinase found in two functionally distinct complexes, mTORC1 and mTORC2, which are differentially regulated by a great number of nutrients such as glucose and amino acids, energy (oxygen and ATP/AMP content), growth factors, hormones, and neurotransmitters. mTOR controls many basic cellular functions such as protein synthesis, energy metabolism, cell size, lipid metabolism, autophagy, mitochondria, and lysosome biogenesis. In addition, mTOR-controlled signaling pathways regulate many integrated physiological functions of the nervous system including neuronal development, synaptic plasticity, memory storage, and cognition. Thus it is not surprising that deregulation of mTOR signaling is associated with many neurological and psychiatric disorders. Preclinical and preliminary clinical studies indicate that inhibition of mTORC1 can be beneficial for some pathological conditions such as epilepsy, cognitive impairment, and brain tumors, whereas stimulation of mTORC1 (direct or indirect) can be beneficial for other pathologies such as depression or axonal growth and regeneration.

Intermittent metabolic switching, neuroplasticity and brain health

“…A highly conserved pathway by which cells regulate protein synthesis in response to fluctuations in nutrient availability (principally glucose and amino acids) involves a protein called mechanistic target of rapamycin (mTOR; also known as serine/threonine-protein kinase mTOR (MTOR) and mammalian target of rapamycin) 71,72 . In the fed state, activation of mTOR by upstream nutrient-sensing proteins activates ribosomal protein S6 kinase to increase general protein synthesis and activates sterol regulatory element-binding protein (SREBP1; also known as SREBF1) to increase lipid synthesis.…”

Physical interaction between neurofibromin and serotonin 5-HT 6 receptor promotes receptor constitutive activity

“…Loss of neurofibromin Ras-GAP activity in NF1 leads to aberrant mTOR activation, which is essential for NF1-associated malignancies (34). Moreover, nonphysiological mTOR activation has been involved in cognitive deficits observed in several neurodevelopmental disorders (35). mTOR activation, under the control of 5-HT 6 receptor, likewise underlies deficits in social cognition and episodic memory in rat developmental models of schizophrenia (12).…”

Dysregulation of the (immuno)proteasome pathway in malformations of cortical development

“…The innate and adaptive immune responses have also been shown to be influenced by the mTOR pathway [55–57]. Moreover, the mTOR complex 1 (mTORC1) has been identified as a key regulator of autophagy [58, 59], a pathway which is defective in FCD II and TSC [60]. Increasing evidence indicates a strong relationship with tight coordination between the autophagy and the proteasome system [61].…”