# Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain
## 3 Rheb-mTOR Signaling in the Brain  
Tuberous sclerosis (TS) disease, also called TSC, is a genetic disorder characterized by the growth of numerous noncancerous tumors in many parts of the body [37]. TSC1 and TSC2, intracellular molecules named after TSC, are associated with the activation of Rheb/mTOR signaling pathway [24; 25]. The activity of Rheb is regulated by TSC2, which acts as a guanosine triphosphatase-activating protein (GAP) that enhances the hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate (GDP) by Rheb [24; 38; 39; 40; 41; 42]. The heterodimer of the two proteins is a critical negative regulator of Rheb, resulting in the inhibition of mTOR [43], which is controlled by insulin. Insulin triggers the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Activated Akt then increases TSC2 phosphorylation at serine 939 and 981, leading to the dissociation of TSC1/2 [44]. It is well known that mTOR, a serine/threonine kinase that belongs to the family of PI3K-related kinases, acts as a central protein that controls cell growth and proliferation through transcriptional and translational mechanisms in response to various extracellular stimuli such as amino acids and growth factors [45]. Recently, a study demonstrated the requirement of intact F-actin dynamics for proper mTORC1 activation in response to netrin-1 in the axonal growth cones of tectal neurons [46]. mTORC1 is rapamycin-sensitive and contains regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (mLST8), and the 40 kDa proline-rich Akt substrate (PRAS40) [47; 48]. The downstream targets of mTOR include two independent targets, i.e., ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which play important roles in mRNA translation [49]. mTOR stimulates translational initiation through direct phosphorylation and activation of S6K1 [50] and 4E-BP1 [51]. mTOR has also emerged as an important regulator of various neurological processes including neuronal differentiation, morphogenesis, synaptic plasticity, learning, and memory [52; 53]. The mTOR pathway has been found to adversely affect neural circuit formation. Furthermore, the mTOR pathway regulates axon length [54] and axon guidance in response to environmental signals [55]. Among neurons, local protein synthesis in synapses distant from the soma is mediated by mTOR and is critical for the formation of the neural circuit. The expression levels of synaptic proteins, such as Arc and synapsin, are increased by mTOR activation [56]. The hyperactivation of the mTOR pathway via the loss of _Pten_ has been shown to increase glutamatergic and GABAergic signals [57]. In addition to neurons, the mTOR pathway has been found to regulate glial cells during neural circuit formation. Deletion of the core component of mTORC1 or mTORC2 (_Raptor_ or _Rictor_) was reported to result in defective myelination and oligodendrocyte maturation [58]. mTORC1 activity is important for regulating the organism size and survival during embryonic development. The deficiency of Raptor leads to a reduced brain size in developing embryos due to impaired cell cycle progression and increased apoptosis [59]. Rheb knockout has been observed to cause embryonic lethality in mice. Moreover, mTOR has been reported to be critical for long-lasting forms of neuronal plasticity, such as long-term potentiation (LTP), long-term depression (LTD), and learning and memory, which require protein synthesis [53; 60; 61; 62]. For example, learning transiently increases p-mTOR in the hippocampus [63; 62]. The blockade of mTOR signaling with rapamycin impairs hippocampus-dependent learning in tasks such as inhibitory avoidance [64], and both voluntary [65; 66] and forced exercise enhance learning in the same task [67].