Editors' ChoiceNeuroscience

Memories from Rictor

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Sci. Signal.  09 Apr 2013:
Vol. 6, Issue 270, pp. ec82
DOI: 10.1126/scisignal.2004212

Learning occurs when short-term memories are converted to long-term memories and stored in the hippocampus through a process involving synaptic protein synthesis, modification, and cytoskeletal rearrangement. Several cognitive disorders are characterized by decreased activity of mTORC2 (mammalian target of rapamycin complex 2). Huang et al. showed that mTORC2 promotes actin polymerization to strengthen synaptic connections in the hippocampus during the formation of long-term memories. Mice with a conditional knockout of Rictor, the regulatory subunit of mTORC2 (Rictor fb-KO), had decreased activity of mTORC2 but not mTORC1, which promotes protein synthesis. Although Rictor fb-KO mice showed normal basal synaptic transmission and early long-term potentiation (E-LTP), they were unable to convert E-LTP to late LTP, a critical process in long-term memory formation. Rictor fb-KO mice showed impaired fear conditioning and water maze learning, which are behavioral models of memory formation and storage. Rictor-fb-KO mice showed decreased activity of Rac1 and Cdc42, two Rho guanine triphosphatases that promote actin polymerization. The guanine nucleotide exchange factor Tiam1 bound to mTORC2 in wild-type hippocampal extracts, suggesting that mTORC2 may activate Rac1 by recruiting Tiam1. Disrupting actin polymerization in wild-type mice with cytochalasin-D impaired late LTP formation, whereas promoting actin polymerization in Rictor-fb-KO mice with jasplakinolide restored the production of late LTP. These benefits of jasplakinolide were blocked by treatment with the protein synthesis inhibitor anisomycin, indicating that actin polymerization was upstream of protein synthesis and mTORC1. Selective activation of mTORC2 using a small-molecule compound stimulated late LTP production and increased fear conditioning in wild-type but not Rictor fb-KO mice. Impaired long-term memory formation was also evident in rictor-deficient flies, suggesting that this mechanism is evolutionarily conserved. The findings suggest that mTORC2 strengthens the synaptic actin cytoskeleton to promote long-term memory formation.

W. Huang, P. J. Zhu, S. Zhang, H. Zhou, L. Stoica, M. Galiano, K. Krnjević, G. Roman, M. Costa-Mattioli, mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat. Neurosci. 16, 441–448 (2013).  [PubMed]