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    Home > Active Ingredient News > Study of Nervous System > PNAS: Tsinghua University's Yao Jun team discovered that miRNAs regulate brain hippocampal cognitive function and its mechanism

    PNAS: Tsinghua University's Yao Jun team discovered that miRNAs regulate brain hippocampal cognitive function and its mechanism

    • Last Update: 2021-04-14
    • Source: Internet
    • Author: User
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    MicroRNA (miRNA) plays an important role in the development and functional regulation of the nervous system, and is an integral part of its normal operation.

    Among them, miR-218, as a miRNA widely expressed in the central nervous system, has been found to have abnormal expression in a variety of neurodegenerative and neuropsychiatric diseases such as Alzheimer's disease, schizophrenia and depression.

    In these diseases, the cognitive function of patients has varying degrees of defects.

    However, the role of miR-218 in these diseases is still unknown.

    On March 29, 2021, the Yao Jun Laboratory of the School of Life Sciences, Tsinghua University, published a titled miR-218-2 regulates cognitive functions in the hippocampus through complement component 3–dependent modulation of synaptic in the Proceedings of the National Academy of Sciences (PNAS) Research paper on vesicle release.

    This study shows that miR-218-2 gene regulates neuronal morphology and the transport and release of synaptic vesicles through the target gene C3 in the mouse hippocampus, thereby affecting the synaptic reversibility of neurons and the occurrence of LTP, and ultimately affects Cognitive function of mice.

    The study revealed that neurodegenerative diseases and neuropsychiatric diseases may produce cognitive impairment through a common miR-218-related mechanism, which provides new ideas and directions for the treatment of cognitive deficits in subsequent diseases.

    The research team used CRISPR/Cas9 gene editing technology to construct miR-218-1 and miR-218-2 gene knockout mice, revealing that miR-218 is widely expressed in the brain, especially in the hippocampus.
    After miR-218-2 gene, the expression level of miR-218 in the hippocampus decreased significantly.

    Subsequently, through conditioned fear experiments, water maze and T maze behavior tests, it was found that the cognitive ability of miR-218-2 knockout mice was obviously defective.

    In addition, the overexpression of miR-218 in the hippocampus of mice by virus injection will enable the mice to exhibit enhanced cognitive functions in behavioral tests.

    In order to clarify the molecular mechanism of cognitive deficits in miR-218-2 knockout mice, the authors used whole-cell patch clamp technology, Golgi staining and cryo-electron microscopy to analyze the development, morphology, and morphology of miR-218-2 knockout neurons.
    Electrophysiological characteristics, found that in the hippocampal neurons knocked out by miR-218-2, the release of excitatory synapses of synaptic vesicles is reduced, and the long-term potentiation (LTP), which is the basis of learning and memory molecules, is weakened; miR-218-2 is missing The total length of dendrites and the number of branches of neurons decreased, and the density of synapses increased; and the results of electron microscopy analysis showed that the transport and distribution of synaptic vesicles in miR-218-2 knockout neurons were defective.

    In addition, overexpression of miR-218 will lead to the opposite neuronal phenotype.

    Furthermore, the authors combined RNAseq and miR-218 target gene prediction data and performed KEGG analysis to screen out possible miR-218 target genes.

    Using qRT-PCR and dual-luciferase reporter gene analysis, it was confirmed that the three genes of complement factor C3, Mmp13 and Gdnf are miR-218 candidate target genes.

    After verification by electrophysiological experiments, it was found that only the phenotypes of C3 knockdown neurons were completely consistent with miR-218 overexpressing neurons.

    Direct treatment of wild-type mice with C3 protein peptides can mimic the behavior and cell phenotype of miR-218-2 knockout mice, while treatment of miR-218-2 knockout mice with C3a receptor antagonist SB290157 can mimic the behavior and cell phenotype of miR-218-2 knockout mice.
    Rescue the synaptic function and cognitive deficits of miR-218-2 gene knockout mice.

    Therefore, the research team concluded that complement factor C3 is the main target gene for miR-218 to regulate synaptic function.

    miR-218 regulates the cognitive function of the hippocampus through C3.
    In summary, the miR-218-2 gene in the mouse hippocampus regulates the morphology of neurons and the transport and release of synaptic vesicles through the target gene C3, thereby affecting neuronal development.
    The occurrence of synaptic reversibility and LTP ultimately affects the cognitive function of mice.

    The study revealed that neurodegenerative diseases and neuropsychiatric diseases may produce cognitive impairment through a common miR-218-related mechanism, which provides new ideas and directions for the treatment of cognitive deficits in subsequent diseases.

    Researcher Yao Jun, School of Life Sciences, Tsinghua University, is the corresponding author of this article.

    Lu Siyao, a doctoral student in the School of Life Sciences, is the first author of this article.

    Postdoctoral fellows Shen Wei, Wang Qiuwen, and Chen Yanfen of School of Life Sciences, Tsinghua University, Ph.
    D.
    students Fu Chonglei, Chen Yun, Liu Yaonan, Researcher Mi Shuangli of Beijing Institute of Genomics, Chinese Academy of Sciences, PhD student Liang Liang, and Researcher Shi Wei of Beihang University contributed to this research An important contribution.

    Link to the paper:
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