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Plexin-A1 expression in the inhibitory neurons of infralimbic cortex regulates the specificity of fear memory in male mice

Abstract

Maintaining appropriate levels of fear memory specificity is crucial for individual’s survival and mental health, whereas overgeneralized fear commonly occurs in neuropsychiatric disorders, including posttraumatic stress disorder and generalized anxiety disorder. However, the molecular mechanisms regulating fear memory specificity remain poorly understood. The medial prefrontal cortex (mPFC) is considered as a key brain region in fear memory regulation. Previous transcriptomic studies have identified that plexin-A1, a transmembrane receptor critical for axon development, was downregulated in the mPFC after fear memory training. In this study, we identified that learning-induced downregulation of the mRNA and protein levels of plexin-A1 specifically occurred in the inhibitory but not excitatory neurons in the infralimbic cortex (IL) of mPFC. Further studies of plexin-A1 by virus-mediated over-expression of functional mutants selectively in the IL inhibitory neurons revealed the critical roles of plexin-A1 for regulating memory specificity and anxiety. Moreover, our findings revealed that plexin-A1 regulated the distribution of glutamic acid decarboxylase 67, a GABA synthetase, which in turn modulated the activity of IL and its downstream brain regions. Collectively, our findings elucidate the molecular modifier of IL inhibitory neurons in regulating memory specificity and anxiety, and provide candidates for developing therapeutic strategies for the prevention or treatment of a series of fear generalization-related neuropsychiatric disorders.

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Fig. 1: CFC training reduces Plxna1 expression in the mPFC.
Fig. 2: PLXNA1 level decreases in the inhibitory neurons of the IL deep layers at 1 h after CFC.
Fig. 3: PLXNA1 in the IL inhibitory neurons regulates memory specificity.
Fig. 4: PLXNA1 in the IL inhibitory neurons regulates c-FOS expression in the IL and downstream brain regions.
Fig. 5: PLXNA1 in the inhibitory neurons modulates the number of GAD67+ puncta in the IL.

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Acknowledgements

We thank the animal facility and the core facility of the Zhongshan School of Medicine, Sun Yat-sen University for technical assistance. We thank all members of the Ye lab and Lin lab for valuable discussions and technical assistance during the execution of this projection. Supported in part by grants from National Natural Science Foundation of China (No. 81873797 to XY, No. 81972967 to WJL), Natural Science Foundation of Guangdong Province (No. 2019A1515011483 to XY, No. 2019A1515011754 to WJL), the Fundamental Research Funds for the Central Universities (No. 19ykzd40 to XY), Guangdong Project (No. 2019QN01Y202 to XY), Science and Technology Program of Guangzhou (No. 202007030001 to XY and WJL). The authors report no biomedical financial interests or potential conflicts of interest.

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XY and WJL designed the research project. XC, YZ, SZ, PZ and XY performed the experiments. XC, YZ, SZ, PZ, JLZ and WW analyzed the data. XY and WJL wrote the paper with input from XC, YZ, SZ, PZ and WW.

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Correspondence to Xiaojing Ye.

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Cheng, X., Zhao, Y., Zheng, S. et al. Plexin-A1 expression in the inhibitory neurons of infralimbic cortex regulates the specificity of fear memory in male mice. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01177-1

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