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Astrocytes Mediate Cholinergic Regulation of Adult Hippocampal Neurogenesis and Memory Through M1 Muscarinic Receptor

  • Wei-Peng Li
    Affiliations
    State Key Laboratory of Organ Failure Research, Institutes of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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  • Xiao-Hong Su
    Affiliations
    State Key Laboratory of Organ Failure Research, Institutes of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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  • Neng-Yuan Hu
    Affiliations
    State Key Laboratory of Organ Failure Research, Institutes of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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  • Jian Hu
    Affiliations
    State Key Laboratory of Organ Failure Research, Institutes of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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  • Xiao-Wen Li
    Affiliations
    State Key Laboratory of Organ Failure Research, Institutes of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Jian-Ming Yang
    Correspondence
    Address correspondence to Jian-Ming Yang, Ph.D.
    Affiliations
    State Key Laboratory of Organ Failure Research, Institutes of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Tian-Ming Gao
    Correspondence
    Tian-Ming Gao, M.D., Ph.D.
    Affiliations
    State Key Laboratory of Organ Failure Research, Institutes of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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      Abstract

      Background

      In the neurogenic niches of the adult hippocampus, new functional neurons are continuously generated throughout life, and generation of these neurons has been implicated in learning and memory. Astrocytes, as components of the neurogenic niches, are critical in the regulation of adult hippocampal neurogenesis (AHN). However, little is known about how astrocytes receive and respond to extrinsic cues to regulate AHN.

      Methods

      By using a transgenic strategy to conditionally delete astrocytic CRHM1 in mice and AAV (adeno-associated virus)–mediated overexpression of astrocytic CHRM1 specifically in the hippocampal dentate gyrus, we systematically investigated the role of astrocytic CHRM1 in the regulation of AHN and the underlying mechanisms using the combined approaches of immunohistochemistry, retrovirus labeling, electrophysiology, primary astrocyte cultures, immunoblotting, and behavioral assays.

      Results

      We report that genetic ablation of CHRM1 in astrocytes led to defects in neural stem cell survival, neuronal differentiation, and maturation and integration of newborn neurons in the dentate gyrus. Astrocytic CHRM1-mediated modulation of AHN was mediated by BDNF (brain-derived neurotrophic factor) signaling. Furthermore, CHRM1 ablation in astrocytes impaired contextual fear memory. These impairments in both AHN and memory were rescued by overexpression of astrocytic CHRM1 in the dentate gyrus.

      Conclusions

      Our findings reveal a critical role for astrocytes in mediating cholinergic regulation of AHN and memory through CHRM1.

      Keywords

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