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首页> 外文期刊>PLoS Genetics >The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors
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The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors

机译：癫痫和智障残疾相关蛋白质TBC1D24调节兴奋性突触和动物行为的维持

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Perturbation of synapse development underlies many inherited neurodevelopmental disorders including intellectual disability (ID). Diverse mutations on the human TBC1D24 gene are strongly associated with epilepsy and ID. However, the physiological function of TBC1D24 in the brain is not well understood, and there is a lack of genetic mouse model that mimics TBC1D24 loss-of-function for the study of animal behaviors. Here we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6. Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety. Interestingly, we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution. We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death. Moreover, the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory. Our findings therefore uncover a previously uncharacterized postsynaptic function of TBC1D24, and suggest that impaired dendritic spine maintenance contributes to the pathophysiology of individuals harboring TBC1D24 gene mutations. The F251L knock-in mice represent a useful animal model for investigation of the mechanistic link between TBC1D24 loss-of-function and neurodevelopmental disorders.
机译：Synapse开发的扰动是包括智力残疾（ID）的许多遗传性神经发育障碍。人TBC1D24基因上的不同突变与癫痫和ID强烈相关。然而，大脑中TBC1D24的生理功能尚不清楚，并且缺乏遗传小鼠模型，用于研究动物行为研究的TBC1D24功能丧失。在这里，我们报告说，TBC1D24存在于兴奋性突触的突触突触部位，其中通过抑制小GTP酶ARF6维持树突刺。在成年海马显示树突血管损失中进行病毒介导的TBC1D24的小鼠，在语境恐惧记忆中缺乏缺陷，以及异常行为，包括多动和焦虑增加。有趣的是，我们表明TBC1D24的蛋白质稳定性由疾病相关的畸形突变减少，导致F251L氨基酸取代。我们进一步产生了F251L敲击小鼠，纯合突变体显示出增加的神经元兴奋性，自发性癫痫发作和预成熟死亡。此外，杂合F251L敲入小鼠存活到成年内，但显示树突脊柱缺陷和损伤记忆。因此，我们的研究结果揭示了TBC1D24的先前无表特征的突触函数，并表明树突脊柱维持受损导致患TBC1D24基因突变的个体的病理生理学。 F251L敲入小鼠代表了一种有用的动物模型，用于调查TBC1D24丧失功能丧失和神经发育障碍之间的机械联系。

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