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CPEB3-dowregulated Nr3c1 mRNA translation confers resilience to developing posttraumatic stress disorder-like behavior in fear-conditioned mice

Abstract

Susceptibility or resilience to posttraumatic stress disorder (PTSD) depends on one’s ability to appropriately adjust synaptic plasticity for coping with the traumatic experience. Activity-regulated mRNA translation synthesizes plasticity-related proteins to support long-term synaptic changes and memory. Hence, cytoplasmic polyadenylation element-binding protein 3-knockout (CPEB3-KO) mice, showing dysregulated translation-associated synaptic rigidity, may be susceptible to PTSD-like behavior. Here, using a context-dependent auditory fear conditioning and extinction paradigm, we found that CPEB3-KO mice exhibited traumatic intensity-dependent PTSD-like fear memory. A genome-wide screen of CPEB3-bound transcripts revealed that Nr3c1, encoding glucocorticoid receptor (GR), was translationally suppressed by CPEB3. Thus, CPEB3-KO neurons with elevated GR expression exhibited increased corticosterone-induced calcium influx and decreased mRNA and protein levels of brain-derived neurotrophic factor (Bdnf). Moreover, the reduced expression of BDNF was associated with increased GR level during fear extinction in CPEB3-KO hippocampi. Intracerebroventricular delivery of BDNF before extinction training mitigated spontaneous fear intrusion in CPEB3-KO mice during extinction recall. Analysis of two GEO datasets revealed decreased transcriptomic expression of CPEB3 but not NR3C1 in peripheral blood mononuclear cells of humans with PTSD. Collectively, this study reveals that CPEB3, as a potential PTSD-risk gene, downregulates Nr3c1 translation to maintain proper GR-BDNF signaling for fear extinction.

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Fig. 1: CPEB3-KO mice show PTSD-like behavior in response to intensified fear conditioning.
Fig. 2: Analysis of CPEB3-bound transcripts involved in learning and memory.
Fig. 3: CPEB3 deficiency elevates translation of GR mRNA in neurons.
Fig. 4: Elevated GR signaling and decreased Bdnf expression in CPEB3-KO hippocampus.
Fig. 5: Reduced BDNF signaling during fear extinction contributes to PTSD-like behavior in CPEB3-KO mice.

Data availability

Microarray data can be viewed in GEO accession GSE159731.

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Acknowledgements

The authors thank Huei-Fang Wu in NPAS Neuro-Electrophysiology Core for calcium imaging, the institutional pathology core for brain tissue sectioning, and DNA sequencing support under the Academia Sinica Core Facility and Innovative Instrument Project (AS-CFII-108-115).

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W.-H.L. H.-W.C. designed and conducted the experiments, analyzed data and wrote the manuscript. P-Y Lin identified PTSD-like phenotype, S-H Lin, H-W Chen and T-H Liu helped with some experiments and analyses. Y.-S.H. designed and supervised the study and co-wrote the manuscript with H.-W.C. and W.-H.L. and is responsible for its content.

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Correspondence to Yi-Shuian Huang.

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Lu, WH., Chao, HW., Lin, PY. et al. CPEB3-dowregulated Nr3c1 mRNA translation confers resilience to developing posttraumatic stress disorder-like behavior in fear-conditioned mice. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01017-2

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