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Prevention of the return of extinguished fear by disrupting the interaction of neuronal nitric oxide synthase with its carboxy-terminal PDZ ligand

Molecular Psychiatry volume 26, pages 6506–6519 (2021)Cite this article

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Abstract

Exposure therapy based on the extinction of fear memory is first-line treatment for post-traumatic stress disorder (PTSD). However, fear extinction is relatively easy to learn but difficult to remember, extinguished fear often relapses under a number of circumstances. Here, we report that extinction learning-induced association of neuronal nitric oxide synthase (nNOS) with its carboxy-terminal PDZ ligand (CAPON) in the infralimbic (IL) subregion of medial prefrontal cortex negatively regulates extinction memory and dissociating nNOS-CAPON can prevent the return of extinguished fear in mice. Extinction training significantly increases nNOS-CAPON association in the IL. Disruptors of nNOS-CAPON increase extracellular signal-regulated kinase (ERK) phosphorylation and facilitate the retention of extinction memory in an ERK2-dependent manner. More importantly, dissociating nNOS-CAPON after extinction training enhances long-term potentiation and excitatory synaptic transmission, increases spine density in the IL, and prevents spontaneous recovery, renewal and reinstatement of remote fear of mice. Moreover, nNOS-CAPON disruptors do not affect other types of learning. Thus, nNOS-CAPON can serve as a new target for treating PTSD.

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Fig. 1: Extinction learning-induced nNOS-CAPON association in the IL negatively regulates extinction memory.
Fig. 2: nNOS-CAPON association weakens extinction memory through inhibiting ERK2 but not ERK1.
Fig. 3: Dissociating CAPON from nNOS enhances synaptic plasticity in the IL.
Fig. 4: Dissociating CAPON from nNOS prevents spontaneous recovery of remote fear.
Fig. 5: Dissociating CAPON from nNOS reduces renewal and reinstatement of remote fear.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (31530091, 81870912), National Key Research and Development Program of China (2016YFC1306703), Science and Technology Program of Guangdong (2018B030334001) and by the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.

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  1. These authors contributed equally: Cheng Qin, Xin-Lan Bian and Hai-Yin Wu

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China

    Cheng Qin, Xin-Lan Bian, Hai-Yin Wu, Jia-Yun Xian, Yu-Hui Lin, Cheng-Yun Cai, Ying Zhou, Xiao-Lin Kou, Lei Chang, Chun-Xia Luo & Dong-Ya Zhu

  2. Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, China

    Ting-You Li

  3. Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, China

    Dong-Ya Zhu

  4. Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China

    Dong-Ya Zhu

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Contributions

D-YZ designed experiments; CQ, XLB, HYW, JYX, YHL, CYC, YZ and XLK performed research; LC and CXL contributed unpublished reagents/analytic tools; TYL provided a small molecular nNOS-CAPON disruptor ZLc-002; CQ and XLB analyzed data; D-YZ wrote the paper. D-YZ supervised the research.

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Correspondence to Dong-Ya Zhu.

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Qin, C., Bian, XL., Wu, HY. et al. Prevention of the return of extinguished fear by disrupting the interaction of neuronal nitric oxide synthase with its carboxy-terminal PDZ ligand. Mol Psychiatry 26, 6506–6519 (2021). https://doi.org/10.1038/s41380-021-01118-w

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