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    Home > Active Ingredient News > Study of Nervous System > Science: The molecular mechanism of PCDH19 gene mutations causing synaptic dysfunction in female Dravet syndrome

    Science: The molecular mechanism of PCDH19 gene mutations causing synaptic dysfunction in female Dravet syndrome

    • Last Update: 2021-05-22
    • Source: Internet
    • Author: User
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    PCDH19 gene mutation was first discovered in a family of women with epilepsy and mental retardation in 2008.
    PCDH19 mutation usually presents cognitive dysfunction, and epilepsy symptoms also exist in the early stage.
    About 70% of patients have mental retardation.

    PCDH19 gene mutation is a special X-linked inheritance mode: heterozygous women who carry this gene mutation develop the disease, while hemizygous men who carry this mutation do not.

    On April 16, 2021, Hisashi Umemori's research team at Harvard Medical School's Boston Children's Hospital published an article in Science, revealing the previously undiscovered molecular mechanism of cognitive dysfunction caused by mutations in the PCDH19 gene.

    PCDH19 expression in the brain PCDH19 mediates calcium-dependent intercellular adhesion through homologous binding of extracellular cadherin (EC) domains.

    In situ hybridization experiments found that PCDH19 is highly expressed on the mossy fiber synapses in the fifth layer of the cortex and hippocampus, and on the pre-synaptic and post-synaptic structures.

    In addition, the expression of PCDH19 gradually increases during development.

    Thy1-GFP-M transgenic mice can mark mossy fibers in the hippocampus.

    Using this tool mouse, they found that the PCDH19 gene mutation heterozygous female mice (Pcdh19-HET female), but not the PCDH19 gene mutation hemizygous male mice, had a significant decrease in the number of mossy fiber synapses during development.

    In addition, the number of presynaptic vesicles in Pcdh19-HET female mice was significantly reduced, but the post-synaptic synaptic density did not change.

    Electrophysiological experiments found that the frequency of small excitatory postsynaptic currents in hippocampal neurons of Pcdh19-HET female mice decreased, but the amplitude did not change (frequency can represent pre-synaptic function, and amplitude represents post-synaptic function).

    What's more serious is that the long-term potentiation effect of the female mouse does not exist.

    This indicates that Pcdh19-HET female mice have obstacles in the presynaptic structure of mossy fibers during development.

    Previous studies have shown that synaptic dysfunction in hippocampal mossy fibers causes cognitive dysfunction.

    Researchers conducted conditioned fear memory and situational fear memory training on the above mutant mice, and found that Pcdh19-HET female mice did not have memory impairment.

    Compared with unfamiliar clues, the situational fear memory training of pattern separation allows people to quickly identify a familiar but vague clue, which is called pattern completion.

    The researchers exposed the mice to the environment for subsequent situational fear memory.
    Normal mice have good pattern completion ability, but Pcdh19-HET female mice have impaired this ability.

    In another situational fear memory called pattern separation, Pcdh19-HET female mice cannot distinguish between environmental differences normally.

    PCDH19 forms a cis complex with N-cadherin (Ncad or CDH2), which may mask the binding ability of Ncad.

    The researchers found that the ability of Ncad to transmit intracellular signals in hemizygous male mice with PCDH19 mutations was not obscured.

    But the function of Ncad in Pcdh19-HET female mice was completely masked.

    PCDH19-Ncad colocalization and expression The researchers found that about 80% of PCDH19-Ncad colocalization occurred in normal mice and PCDH19 mutant hemizygous male mice, but this colocalization was significantly reduced in Pcdh19-HET female mice.

    A human embryonic kidney (HEK) cell-neuron co-culture system is adopted: HEK cells overexpressing only Ncad or PCDH19-Ncad at the same time are co-cultured with hippocampal neurons of normal mice that endogenously express PCDH19.

    The results showed that the synaptic density of HEK cells overexpressing Ncad was significantly lower than that of HEK cells overexpressing PCDH19-Ncad at the same time.

    In addition, overexpression of Pcdh19-HET female mouse Ncad by viral vector tool can reverse its synaptic dysfunction.

    This indicates that the PCDH19-Ncad mismatch affects the development of synapses.

    In summary, this article reveals a new molecular mechanism of the female-specific PCDH19 disease model: PCDH19-Ncad mismatches cause synaptic dysfunction and eventually cognitive dysfunction.

    [References] 1.
    https://doi.
    org/10.
    1126/science.
    aaz3893 The pictures in the article are all from the references
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