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GluA1 phosphorylation at serine 831 in the lateral amygdala is required for fear renewal

Nature Neuroscience volume 16, pages 1436–1444 (2013)Cite this article

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Abstract

Fear renewal, a widely pursued model of post-traumatic stress disorder and phobias, refers to the context-specific relapse of conditioned fear after extinction. However, its molecular mechanisms are largely unknown. We found that renewal-inducing stimuli, generally believed to be insufficient to induce synaptic plasticity, enhanced excitatory synaptic strength, activity of synaptic GluA2-lacking AMPA receptors and Ser831 phosphorylation of synaptic surface GluA1 in the lateral nucleus of the amygdala (LAn) of fear-extinguished rats. Consistently, the induction threshold for LAn synaptic potentiation was considerably lowered after extinction, and renewal occluded this low-threshold potentiation. The low-threshold potentiation (a potential cellular substrate for renewal), but not long-term potentiation, was attenuated by dialysis into LAn neurons of a GluA1-derived peptide that competes with Ser831-phosphorylated GluA1. Microinjections of the same peptide into the LAn attenuated fear renewal, but not fear learning. Our findings suggest that GluA1 phosphorylation constitutes a promising target for clinical treatment of aberrant fear-related disorders.

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Figure 1: Renewal-inducing stimuli produce a context-specific enhancement of synaptic efficacy at T-LAn synapses.
Figure 2: Renewal-inducing stimuli enhance the amplitude of AMPAR-mediated mEPSCs at T-LAn synapses in a context-specific manner.
Figure 3: Renewal-inducing stimuli enhance GluA2-lacking AMPAR activity at T-LAn synapses in a context-specific manner.
Figure 4: Renewal-inducing stimuli enhance Ser831 phosphorylation of surface GluA1 in LAn synaptosomes in a context-specific manner.
Figure 5: The presentation of a tone CSt to conditioned rats does not change both synaptic efficacy and GluA1 phosphorylation at LAn synapses.
Figure 6: Induction threshold for T-LAn synaptic potentiation is lowered after extinction of conditioned fear.
Figure 7: The GluA1D peptide inhibits low-threshold potentiation, but not LTP or fear conditioning.
Figure 8: Microinjection of a cell–permeable form of the GluA1D peptide into the LAn attenuates fear renewal.

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Acknowledgements

This paper is dedicated in loving memory to Sang-Soon Choi. We thank P. Sah for his valuable comments on our manuscript. This work was supported by a National Research Foundation of Korea grant funded by the Ministry of Education, Science and Technology (No. 2011-0018209, S.C.), by the Original Technology Research Program for Brain Science through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (No. 2011-0019226, S.C.) and by the Korean World Class Institute program (C.J.L.). B.S., Jeongyeon Kim, K.P., I.H., B.A., S.S., J.L., S.P. and Jihye Kim were supported by Brain Korea 21 Research Fellowships from the Korean Ministry of Education.

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  1. Sukwon Lee, Beomjong Song and Jeongyeon Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea

    Sukwon Lee, Beomjong Song, Ingie Hong, Bobae An, Sangho Song, Jiwon Lee, Sungmo Park, Jihye Kim, Dongeun Park, Kyungjin Kim & Sukwoo Choi

  2. Center for Neural Science and Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul, Korea

    Jeongyeon Kim & C Justin Lee

  3. Department of Biology, Kyunghee University, Seoul, Korea

    Kyungjoon Park & Ki Soon Shin

  4. Department of Life and Nanopharmaceutical Sciences, Kyunghee University, Seoul, Korea

    Kyungjoon Park & Ki Soon Shin

  5. Department of Physiology and Neuroscience, Neuroscience Institute, New York University Langone Medical Center, New York, New York, USA

    Richard W Tsien

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Contributions

S.L., B.S., Jeongyeon Kim, K.K., K.S.S. and S.C. designed the experiments. S.L., B.S., Jeongyeon Kim, K.P., I.H., B.A., S.S., J.L., S.P. and Jihye Kim performed the experiments. S.L., B.S., Jeongyeon Kim, K.K., K.S.S., R.W.T. and S.C. analyzed the data. S.L., B.S., Jeongyeon Kim, D.P., C.J.L., K.K., K.S.S., R.W.T. and S.C. wrote the paper.

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Correspondence to Kyungjin Kim, Ki Soon Shin or Sukwoo Choi.

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Lee, S., Song, B., Kim, J. et al. GluA1 phosphorylation at serine 831 in the lateral amygdala is required for fear renewal. Nat Neurosci 16, 1436–1444 (2013). https://doi.org/10.1038/nn.3491

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