title: ABA renewal involves enhancements in both GluA2-lacking AMPA receptor activity and GluA1 phosphorylation in the lateral amygdala.
abstract: Fear renewal, the context-specific relapse of fear following fear extinction, is a leading animal model of post-traumatic stress disorders (PTSD) and fear-related disorders. Although fear extinction can diminish fear responses, this effect is restricted to the context where the extinction is carried out, and the extinguished fear strongly relapses when assessed in the original acquisition context (ABA renewal) or in a context distinct from the conditioning and extinction contexts (ABC renewal). We have previously identified Ser831 phosphorylation of GluA1 subunit in the lateral amygdala (LA) as a key molecular mechanism for ABC renewal. However, molecular mechanisms underlying ABA renewal remain to be elucidated. Here, we found that both the excitatory synaptic efficacy and GluA2-lacking AMPAR activity at thalamic input synapses onto the LA (T-LA synapses) were enhanced upon ABA renewal. GluA2-lacking AMPAR activity was also increased during low-threshold potentiation, a potential cellular substrate of renewal, at T-LA synapses. The microinjection of 1-naphtylacetyl-spermine (NASPM), a selective blocker of GluA2-lacking AMPARs, into the LA attenuated ABA renewal, suggesting a critical role of GluA2-lacking AMPARs in ABA renewal. We also found that Ser831 phosphorylation of GluA1 in the LA was increased upon ABA renewal. We developed a short peptide mimicking the Ser831-containing C-tail region of GluA1, which can be phosphorylated upon renewal (GluA1S); thus, the phosphorylated GluA1S may compete with Ser831-phosphorylated GluA1. This GluA1S peptide blocked the low-threshold potentiation when dialyzed into a recorded neuron. The microinjection of a cell-permeable form of GluA1S peptide into the LA attenuated ABA renewal. In support of the GluA1S experiments, a GluA1D peptide (in which the serine at 831 is replaced with a phosphomimetic amino acid, aspartate) attenuated ABA renewal when microinjected into the LA. These findings suggest that enhancements in both the GluA2-lacking AMPAR activity and GluA1 phosphorylation at Ser831 are required for ABA renewal.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Kyungjoon
authors.initials: K
authors.lastname: Park
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Beomjong
authors.initials: B
authors.lastname: Song
authors.affiliation: Center for Neural Science and Center for Connectomics, Korea Institute of Science and Technology, Seoul, Korea (ROK).
authors.forename: Jeongyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Ingie
authors.initials: I
authors.lastname: Hong
authors.affiliation: Center for Neural Science and Center for Connectomics, Korea Institute of Science and Technology, Seoul, Korea (ROK).
authors.forename: Sangho
authors.initials: S
authors.lastname: Song
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Junuk
authors.initials: J
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Sungmo
authors.initials: S
authors.lastname: Park
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Bobae
authors.initials: B
authors.lastname: An
authors.affiliation: Department of Anatomy and Brain Korea 21 Biomedical Science program, Korea University, College of Medicine, Seoul, Korea (ROK).
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, Seoul National University, Seoul, Korea (ROK).
authors.forename: Seungbok
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Brain Korea 21 Biomedical Science program, Korea University, College of Medicine, Seoul, Korea (ROK).
authors.forename: Hyun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Center for Neural Science and Center for Connectomics, Korea Institute of Science and Technology, Seoul, Korea (ROK).
authors.forename: Justin C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Sukwon
authors.initials: S
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea (ROK).
authors.forename: Sukwoo
authors.initials: S
authors.lastname: Choi
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D003214:Conditioning, Classical; D005239:Fear; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2