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VGLUT3 neurons in median raphe control the efficacy of spatial memory retrieval via ETV4 regulation of VGLUT3 transcription

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Abstract

The raphe nucleus is critical for feeding, rewarding and memory. However, how the heterogenous raphe neurons are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing VGLUT3. VGLUT3 neurons control the efficacy of spatial memory retrieval by synapsing directly with parvalbumin-expressing GABA interneurons (PGIs) in the dentate gyrus. In a mouse model of Alzheimer’s disease (AD mice), VGLUT3→PGIs synaptic transmission is impaired by ETV4 inhibition of VGLUT3 transcription. ETV4 binds to a promoter region of VGLUT3 and activates VGLUT3 transcription in VGLUT3 neurons. Strengthening VGLUT3→PGIs synaptic transmission by ETV4 activation of VGLUT3 transcription upscales the efficacy of spatial memory retrieval in AD mice. This study reports a novel circuit and molecular mechanism underlying the efficacy of spatial memory retrieval via ETV4 inhibition of VGLUT3 transcription and hence provides a promising target for therapeutic intervention of the disease progression.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31721002, 81920208014, 31930051, 81800133), China Postdoctoral Science Foundation Funded Project (2018M642853). We thank Dr. Min-Hua Luo at Wuhan Institute of Virology, Chinese Academy of Sciences for the construction and generation of the H129ΔTK virus particles.

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Authors and Affiliations

  1. Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Aodi He, Chen Zhang, Xiao Ke, Yao Yi, Quntao Yu, Tongmei Zhang, Hongyan Yu, Huiyun Du, Hao Li, Qing Tian, Ling-Qiang Zhu & Youming Lu

  2. Wuhan Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China

    Aodi He, Chen Zhang, Xiao Ke, Yao Yi, Quntao Yu, Tongmei Zhang, Hongyan Yu, Huiyun Du, Hao Li, Qing Tian, Ling-Qiang Zhu & Youming Lu

  3. Department of Pathophysiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China

    Hao Li, Qing Tian, Ling-Qiang Zhu & Youming Lu

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  1. Aodi He
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  2. Chen Zhang
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He, A., Zhang, C., Ke, X. et al. VGLUT3 neurons in median raphe control the efficacy of spatial memory retrieval via ETV4 regulation of VGLUT3 transcription. Sci. China Life Sci. 65, 1590–1607 (2022). https://doi.org/10.1007/s11427-021-2047-8

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