A recollection of mTOR signaling in learning and memory

Abstract

Mechanistic target of rapamcyin (mTOR) is a central player in cell growth throughout the organism. However, mTOR takes on an additional, more specialized role in the developed neuron, where it regulates the protein synthesis-dependent, plastic changes underlying learning and memory. mTOR is sequestered in two multiprotein complexes (mTORC1 and mTORC2) that have different substrate specificities, thus allowing for distinct functions at synapses. We will examine how learning activates the mTOR complexes, survey the critical effectors of this pathway in the context of synaptic plasticity, and assess whether mTOR plays an instructive or permissive role in generating molecular memory traces.

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

“…31 Transient activation of Akt/mTOR by NMDA and TrkB receptors is required for long-term potentiation of synaptic transmission, however constitutive overexpression of Akt in CA1 is detrimental to learning in rats, possibly because of loss of temporal regulation of Akt. 30,32 Akt can also modulate NMDA/TrkB receptor signaling leading to increased calcium influx after NMDA and BDNF stimulation. 33 Akt and/or mTOR might also facilitate normal learning through NMDA, AMPA, and other receptor trafficking or phosphorylation.…”

Regulation of global and specific mRNA translation by the mTOR signaling pathway

“…[83][84][85][86][87][88] All of these proteins are encoded by TOP mRNAs, 64 suggesting that mTORC1 may participate in synaptic plasticity by locally increasing the availability of translation factors and other components of the translational apparatus. 78 Evidence for this comes from the observation that TOP mRNAs are transported into dendrites and axons where they are locally translated in an mTORC1-dependent manner. 88,89 In fact, TOP mRNAs represent some of the most abundant transcripts localized within these structures.…”

“…[80][81][82] Neuronal mTORC1 becomes activated in response to different stimulation paradigms (i.e., forskolin, high-frequency stimulation, mGluR agonists), and its inhibition by rapamycin was found to block long-lasting synaptic changes and memory consolidation in different animal models. 78 Notably, a number of studies have documented an elevation in the levels of elongation factors eEF1A and eEF2, as well as ribosomal protein S6, in response to synaptic activity in both mammals and Aplysia. [83][84][85][86][87][88] All of these proteins are encoded by TOP mRNAs, 64 suggesting that mTORC1 may participate in synaptic plasticity by locally increasing the availability of translation factors and other components of the translational apparatus.…”

“…78,79 This is likely to be particularly important for synaptic plasticity, such as during the late phase of long-term potentiation (L-LTP), which requires local increases in protein synthesis in response to synaptic activity. [80][81][82] Neuronal mTORC1 becomes activated in response to different stimulation paradigms (i.e., forskolin, high-frequency stimulation, mGluR agonists), and its inhibition by rapamycin was found to block long-lasting synaptic changes and memory consolidation in different animal models.…”

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

“…mTORC1 is a critical cellular energy and nutrient status sensor that integrates signals from multiple pathways to regulate protein, lipid, and nucleotide synthesis, and it has also been identified as an important modulator of learning and memory (Dash et al 2006;Gkogkas et al 2010;Hoeffer and Klann 2010;Graber et al 2013;Santini et al 2014). Previous studies using cultured cells deprived of serum/amino acids have shown that glutamine can either increase or decrease mTORC1 activity (Deldicque et al 2008;Nicklin et al 2009;Kim et al 2013).…”