Palmitoylation of PSD‐95 Orchestrates Learning‐Dependent Metaplasticity in the Amygdala and Fear Memory
Source abstract
Abstract
ABSTRACT Palmitoylation has been implicated in learning and memory processes, yet its precise role and underlying mechanisms remain poorly understood. Here, we report a novel role of palmitoylation in regulating amygdalar synaptic plasticity and fear memory, involving the regulation of palmitate cycling on PSD‐95. Using a series of multi‐methodological experiments, we demonstrated that conditioned fear learning impairs amygdalar metaplasticity—an effect not observed in the hippocampus. Furthermore, PSD‐95 recruits LTP‐like mechanisms at lateral amygdala (LA) synapses, and its palmitoylation is critically involved in fear memory expression. Notably, PSD‐95 palmitoylation contributes to the occlusion of LA‐LTP following fear conditioning. Mechanistically, DHHC2 drives PSD‐95 palmitoylation and modulates LA synaptic plasticity following fear conditioning, whereas PICK1 facilitates the activity‐dependent trafficking of DHHC2 to PSD‐95 at synapses. Collectively, these findings highlight the PICK1‐DHHC2‐PSD‐95 pathway as a critical regulator of learning‐dependent metaplasticity in the LA, which occludes further HFS‐induced LTP while promoting fear memory expression.
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Research context
OpenAlex topics: Neuroscience and Neuropharmacology Research · Memory and Neural Mechanisms · Neurogenesis and neuroplasticity mechanisms
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Pharmacology School of Pharmacy Fujian Medical University Fuzhou China
Key Laboratory of Brain Aging and Neurodegenerative Diseases Fujian Medical University Fuzhou China
School of Basic Medicine and Life Sciences Key Laboratory of Tropical Translational Medicine of Ministry of Education Hainan Medical University Haikou China
Department of Stomatology Union Hospital Fujian Medical University Fuzhou China
Fujian Provincial Institutes of Brain Disorders and Brain Sciences First Affiliated Hospital Fujian Medical University Fuzhou China
Department of Clinical Pharmacy and Pharmacy Administration School of Pharmacy Fujian Medical University Fuzhou China
Beijing Key Laboratory of Intelligent Drug Research and Development for Mental Disorders National Clinical Research Center for Mental Disorders National Center for Mental Disorders Beijing Anding Hospital Capital Medical University Beijing China
School of Pharmaceutical Sciences Hunan Normal University Changsha China
Funding
National Natural Science Foundation of China
References (88)
Show source-provided references
1. 10.31887/DCNS.2015.17.3/bbandelow10.31887/DCNS.2015.17.3/bbandelow ↗
2. 10.1016/S0140‐6736(21)02143‐710.1016/S0140‐6736(21)02143‐7 ↗
3. 10.1016/S0140‐6736(19)30934‐110.1016/S0140‐6736(19)30934‐1 ↗
4. 10.1038/tp.2017.16110.1038/tp.2017.161 ↗
5. 10.1523/JNEUROSCI.1776‐21.202210.1523/JNEUROSCI.1776‐21.2022 ↗
6. 10.1038/sj.mp.400081210.1038/sj.mp.4000812 ↗
7. 10.1038/s41593‐019‐0361‐z10.1038/s41593‐019‐0361‐z ↗
8. 10.1016/j.biopsych.2010.04.02710.1016/j.biopsych.2010.04.027 ↗
9. 10.1016/j.neuron.2017.08.00410.1016/j.neuron.2017.08.004 ↗
10. 10.1038/s41593‐024‐01676‐610.1038/s41593‐024‐01676‐6 ↗
11. 10.1038/3760110.1038/37601 ↗
12. 10.1523/JNEUROSCI.23‐32‐10283.200310.1523/JNEUROSCI.23‐32‐10283.2003 ↗
13. 10.1016/j.celrep.2017.10.04610.1016/j.celrep.2017.10.046 ↗
14. 10.1523/JNEUROSCI.20‐23‐08909.200010.1523/JNEUROSCI.20‐23‐08909.2000 ↗
15. 10.1016/j.neuron.2008.07.00410.1016/j.neuron.2008.07.004 ↗
16. 10.3390/biology1210127410.3390/biology12101274 ↗
17. 10.1038/nrn94010.1038/nrn940 ↗
18. 10.1016/j.plipres.2009.02.00110.1016/j.plipres.2009.02.001 ↗
19. 10.3389/fphar.2023.134283010.3389/fphar.2023.1342830 ↗
20. 10.1016/j.conb.2005.08.00110.1016/j.conb.2005.08.001 ↗
21. 10.1038/nrn278810.1038/nrn2788 ↗
22. 10.1126/sciadv.abb079910.1126/sciadv.abb0799 ↗
23. 10.1016/j.schres.2016.01.05410.1016/j.schres.2016.01.054 ↗
24. 10.1038/ng137510.1038/ng1375 ↗
25. 10.1038/s42003‐025‐08140‐610.1038/s42003‐025‐08140‐6 ↗
26. 10.1038/nature1329410.1038/nature13294 ↗
27. 10.1126/science.aas920410.1126/science.aas9204 ↗
28. 10.1016/j.neuron.2021.07.00310.1016/j.neuron.2021.07.003 ↗
29. 10.1016/s0896‐6273(02)00645‐110.1016/s0896‐6273(02)00645‐1 ↗
30. 10.1038/s41401‐021‐00661‐010.1038/s41401‐021‐00661‐0 ↗
31. 10.1126/science.adt757010.1126/science.adt7570 ↗
32. Fully‐Primed Slowly‐Recovering Vesicles Mediate Presynaptic LTP at Neocortical Neurons10.1073/pnas.2305460120 ↗
33. 10.1152/jn.00526.201110.1152/jn.00526.2011 ↗
34. 10.1523/JNEUROSCI.23‐13‐05503.200310.1523/JNEUROSCI.23‐13‐05503.2003 ↗
35. 10.1523/JNEUROSCI.4733‐03.200410.1523/JNEUROSCI.4733‐03.2004 ↗
36. 10.1016/j.neuropharm.2004.11.01410.1016/j.neuropharm.2004.11.014 ↗
37. 10.1073/pnas.161296311310.1073/pnas.1612963113 ↗
38. 10.1016/j.neuron.2004.12.00510.1016/j.neuron.2004.12.005 ↗
39. 10.1016/j.neuron.2005.06.03510.1016/j.neuron.2005.06.035 ↗
40. 10.1126/scisignal.adn455610.1126/scisignal.adn4556 ↗
41. 10.1016/j.neuron.2017.03.02210.1016/j.neuron.2017.03.022 ↗
42. The Role of Intrinsic Plasticity in Engram Physiology and Temporal Memory Linking10.1523/JNEUROSCI.1160-24.2024 ↗
43. Activity‐Regulated Trafficking of the Palmitoyl‐acyl Transferase DHHC510.1038/ncomms9200 ↗
44. 10.1523/Jneurosci.0419‐16.201610.1523/Jneurosci.0419‐16.2016 ↗
45. 10.1083/jcb.20090310110.1083/jcb.200903101 ↗
46. 10.1083/jcb.20090610110.1083/jcb.200906101 ↗
47. Palmitoylation as a Functional Regulator of Neurotransmitter Receptors10.1155/2018/5701348 ↗
48. 10.1007/s12035‐016‐9745‐110.1007/s12035‐016‐9745‐1 ↗
49. 10.1007/s12272‐019‐01134‐z10.1007/s12272‐019‐01134‐z ↗
50. 10.1038/nn.365710.1038/nn.3657 ↗
51. 10.1523/Jneurosci.1741‐21.202210.1523/Jneurosci.1741‐21.2022 ↗
52. 10.1016/j.celrep.2018.09.08510.1016/j.celrep.2018.09.085 ↗
53. 10.1074/jbc.M111.24389910.1074/jbc.M111.243899 ↗
54. 10.1073/pnas.060930710410.1073/pnas.0609307104 ↗
55. 10.1523/Jneurosci.2442‐11.201110.1523/Jneurosci.2442‐11.2011 ↗
56. 10.1523/Jneurosci.1278‐14.201410.1523/Jneurosci.1278‐14.2014 ↗
57. PSD‐95 Deficiency Disrupts PFC‐associated Function and Behavior during Neurodevelopment10.1038/s41598-019-45971-w ↗
58. 10.1113/jphysiol.2002.03136910.1113/jphysiol.2002.031369 ↗
59. 10.1016/j.neuron.2005.01.00910.1016/j.neuron.2005.01.009 ↗
60. 10.1016/j.neuron.2007.09.00710.1016/j.neuron.2007.09.007 ↗
61. DHHC2 regulates Fear Memory Formation, LTP, and AKAP150 Signaling in the Hippocampus10.1016/j.isci.2023.107561 ↗
62. Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity10.3389/fnmol.2019.00008 ↗
63. 10.1091/mbc.E10‐10‐082410.1091/mbc.E10‐10‐0824 ↗
64. 10.1523/Jneurosci.2243‐14.201510.1523/Jneurosci.2243‐14.2015 ↗
65. Thalamic Input to the Lateral Amygdala Determines the Temporal Window of Fear‐memory Association10.1038/s42003-025-08289-0 ↗
66. 10.1038/s41593‐020‐0620‐z10.1038/s41593‐020‐0620‐z ↗
67. 10.1523/Jneurosci.5616‐10.201110.1523/Jneurosci.5616‐10.2011 ↗
68. Calmodulin Binding to PSD‐95 Downregulates Its Palmitoylation and AMPARs in Long‐Term Depression10.3389/fnsyn.2019.00006 ↗
69. 10.1126/science.119529810.1126/science.1195298 ↗
70. PICK1 Controls Activity‐Dependent Synaptic Vesicle Cargo Retrieval10.1016/j.celrep.2020.108312 ↗
71. 10.1073/pnas.101610310710.1073/pnas.1016103107 ↗
72. 10.1523/JNEUROSCI.3503‐05.200610.1523/JNEUROSCI.3503‐05.2006 ↗
73. 10.1111/ejn.1225910.1111/ejn.12259 ↗
74. 10.1073/pnas.180150411510.1073/pnas.1801504115 ↗
75. 10.1523/Jneurosci.5068‐11.201210.1523/Jneurosci.5068‐11.2012 ↗
76. 10.1083/jcb.148.1.15910.1083/jcb.148.1.159 ↗
77. 10.1126/science.290.5495.136410.1126/science.290.5495.1364 ↗
78. 10.1016/j.biopsych.2019.09.00810.1016/j.biopsych.2019.09.008 ↗
79. 10.1172/JCI17280210.1172/JCI172802 ↗
80. 10.1038/mp.2017.7610.1038/mp.2017.76 ↗
81. Activity‐Dependent Sulfhydration Signal Controls N‐Methyl‐D‐Aspartate Subtype Glutamate Receptor‐Dependent Synaptic Plasticity Increasing D‐Serine Availability10.1089/ars.2016.6936 ↗
82. Induction of LTP Mechanisms in Dually Innervated Dendritic Spines10.1038/s41598-024-66871-8 ↗
83. 10.1016/j.neuron.2014.09.02410.1016/j.neuron.2014.09.024 ↗
84. 10.1016/j.biopsych.2018.09.02410.1016/j.biopsych.2018.09.024 ↗
85. 10.1111/bph.1631810.1111/bph.16318 ↗
86. 10.1038/nn.230010.1038/nn.2300 ↗
87. 10.1111/bph.1327210.1111/bph.13272 ↗
88. 10.1093/bioinformatics/btw51410.1093/bioinformatics/btw514 ↗