Inhibition of spontaneous recovery of fear by mGluR5 after prolonged extinction training
Authors: Chih-Hua Chang
Sheng-Chun Mao
Olivier J Manzoni
Chia-Chen Wu
Po-Wu Gean
M Juliana Orejarena
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: fear behavior; extinction training; fear recovery; mGluR5; memory
Affiliations: Institute of Basic Medical Sciences and Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan.

Abstract:  Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1-/- mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR2(3Y), a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias. 

Retracted: No

PubPeer comments:
 This paper has a 2013 correction for a misspelled author name. But there might be an additional problem in Figure 6. * Red boxes: The PSD-95 panel in Figure 6C looks similar to the SAP-97 panel in Figure 6D. The Actin panels also look similar, but that is expected. ![file] , 
 These experiments were done by the first author S-C Mao, who got Ph.D. degree in 2008 and moved to drug company in 2010. I tried to reach him and fortunately he responded to me very quickly. From his original figures, I believe that I misplaced the traces when I submitted the manuscript. I will ask the Journal to see if I can make correction. ![file] ![file] , 
 Retraction, 29 July 2020: https: journals.plos.org plosone article?id=10.1371 journal.pone.0237058 It reads:  Following the publication of this article [1], concerns were raised regarding Figs 5 and 6: The bands in the left panel of Fig 5C appear similar to the bands in the right panel of Fig 5C. The authors state that there are differences between the backgrounds of the blots, indicating these are different blots, but no explanation has been provided regarding the level of similarity between the bands in the left and the right blot. The figure legend of Fig 5 states that S and I values were normalised to total protein for quantification, but the total protein control sample appears to be missing from the blots presented in Fig 5C. The PSD-95 panel and the Actin panel of Fig 6C look similar to the SAP-97 panel and the Actin panel of Fig 6D respectively. The authors indicated that the same panels from Fig 6C were used for Fig 6D inadvertently and have provided replacement panels for Fig 6D. The individual level data for Fig 5A and 5B, as well as Fig 6Au20136D have been provided by the authors, but the original uncropped blots underlying the blots presented in Figs 5A, 5C, 6B, 6C and 6D are no longer available. In light of the concerns affecting multiple figure panels that question the integrity of these data, the PLOS ONE Editors retract this article. CHC, OJM, and PWG agreed with the retraction. SCM, CCW, and MJO either did not respond directly or could not be reached. , 
 I have written a letter to the Journal and provided the correct blots to make correction. Unfortunately, Editor decide to retract the paper. I have sent an e-mail to the co-authors to make sincere apology to all of them. I also apology to all the reader. Because of my mistake, the same blots appeared in the same figure, resulting in the retraction of paper. , 
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0237058 Following the publication of this article [1], concerns were raised regarding Figs 5 and 6: The bands in the left panel of Fig 5C appear similar to the bands in the right panel of Fig 5C. The authors state that there are differences between the backgrounds of the blots, indicating these are different blots, but no explanation has been provided regarding the level of similarity between the bands in the left and the right blot. The figure legend of Fig 5 states that S and I values were normalised to total protein for quantification, but the total protein control sample appears to be missing from the blots presented in Fig 5C. The PSD-95 panel and the Actin panel of Fig 6C look similar to the SAP-97 panel and the Actin panel of Fig 6D respectively. The authors indicated that the same panels from Fig 6C were used for Fig 6D inadvertently and have provided replacement panels for Fig 6D. The individual level data for Fig 5A and 5B, as well as Fig 6Au20136D have been provided by the authors, but the original uncropped blots underlying the blots presented in Figs 5A, 5C, 6B, 6C and 6D are no longer available. In light of the concerns affecting multiple figure panels that question the integrity of these data, the PLOS ONE Editors retract this article. CHC, OJM, and PWG agreed with the retraction. SCM, CCW, and MJO either did not respond directly or could not be reached. Reference 1.Mao S-C, Chang C-H, Wu C-C, Orejanera MJ, Manzoni OJ, Gean P-W (2013) Inhibition of Spontaneous Recovery of Fear by mGluR5 after Prolonged Extinction Training. PLoS ONE 8(3): e59580. https: doi.org 10.1371 journal.pone.0059580 ,