AMPA Receptor Expression Requirement During Long-Term Memory Retrieval and Its Association with mTORC1 Signaling
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AMPA Receptor Expression Requirement During Long-Term Memory Retrieval and Its Association with mTORC1 Signaling Magdalena Pereyra 1,2 & Ana Belén de Landeta 1,2 & Juliana Fátima Dalto 1,2 & Cynthia Katche 1,2 & Jorge H. Medina 1,2 Received: 10 June 2020 / Accepted: 16 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Recently, it was reported that mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity during memory retrieval is required for normal expression of aversive and non-aversive long-term memories. Here we used inhibitoryavoidance task to evaluate the potential mechanisms by which mTORC1 signaling pathway participates in memory retrieval. First, we studied the role of GluA-subunit trafficking during memory recall and its relationship with mTORC1 pathway. We found that pretest intrahippocampal infusion of GluR23ɣ, a peptide that selectively blocks GluA2-containing AMPA receptor (AMPAR) endocytosis, prevented the amnesia induced by the inhibition of mTORC1 during retrieval. Additionally, we found that GluA1 levels decreased and GluA2 levels increased at the hippocampal postsynaptic density subcellular fraction of rapamycin-infused animals during memory retrieval. GluA2 levels remained intact while GluA1 decreased at the synaptic plasma membrane fraction. Then, we evaluated the requirement of AMPAR subunit expression during memory retrieval. Intrahippocampal infusion of GluA1 or GluA2 antisense oligonucleotides (ASO) 3 h before testing impaired memory retention. The memory impairment induced by GluA2 ASO before retrieval was reverted by GluA23ɣ infusion 1 h before testing. However, AMPAR endocytosis blockade was not sufficient to compensate GluA1 synthesis inhibition. Our work indicates that de novo GluA1 and GluA2 AMPAR subunit expression is required for memory retrieval with potential different roles for each subunit and suggests that mTORC1 might regulate AMPAR trafficking during retrieval. Our present results highlight the role of mTORC1 as a key determinant of memory retrieval that impacts the recruitment of different AMPAR subunits. Keywords mTORC1-memory retrieval . AMPA receptor-hippocampus . protein synthesis . AMPA receptor trafficking
Introduction The ability to recall past events is essential for several adaptive behaviors. Memory retrieval refers to a dynamic process that allows the access to stored information in the brain. Although the accurate molecular mechanisms underlying memory retrieval are to date poorly described, previous work has pointed to the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) as a critical regulator for the recall of long-term memory (LTM) in the hippocampus, the retrosplenial cortex, and in the amygdala [1, 2].
* Jorge H. Medina [email protected] 1
Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
2
Instituto de Biología Celular y Neurociencia “Dr. Eduardo De Robertis” (IBCN), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
mTORC1 is a serine/threonine
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