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首页> 外文期刊>Molecular brain >Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
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Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients

机译：锌-金属蛋白酶-BDNF轴异常可能会导致年轻的自闭症谱系障碍患者的巨脑和皮质超连通性

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Whereas aberrant brain connectivity is likely the core pathology of autism-spectrum disorder (ASD), studies do not agree as to whether hypo- or hyper-connectivity is the main underlying problem. Recent functional imaging studies have shown that, in most young ASD patients, cerebral cortical regions appear hyperconnected, and cortical thickness/brain size is increased. Collectively, these findings indicate that developing ASD brains may exist in an altered neurotrophic milieu. Consistently, some ASD patients, as well as some animal models of ASD, show increased levels of brain-derived neurotrophic factor (BDNF). However, how BDNF is upregulated in ASD is unknown. To address this question, we propose the novel hypothesis that a putative zinc-metalloprotease-BDNF (ZMB) axis in the forebrain plays a pivotal role in the development of hyperconnectivity and megalencephaly in ASD. We have previously demonstrated that extracellular zinc at micromolar concentrations can rapidly increase BDNF levels and phosphorylate the receptor tyrosine kinase TrkB via the activation of metalloproteases. The role of metalloproteases in ASD is still uncertain, but in fragile X syndrome, a monogenic disease with an autistic phenotype, the levels of MMP are increased. Early exposure to lipopolysaccharides (LPS) and other MMP activators such as organic mercurials also have been implicated in ASD pathogenesis. The resultant increases in BDNF levels at synapses, especially those involved in the zinc-containing, associative glutamatergic system may produce abnormal brain circuit development. Various genetic mutations that lead to ASD are also known to affect BDNF signaling: some down-regulate, and others up-regulate it. We hypothesize that, although both up- and down-regulation of BDNF may induce autism symptoms, only BDNF up-regulation is associated with the hyperconnectivity and large brain size observed in most young idiopathic ASD patients. To test this hypothesis, we propose to examine the ZMB axis in animal models of ASD. Synaptic zinc can be examined by fluorescence zinc staining. MMP activation can be measured by in situ zymography and Western blot analysis. Finally, regional levels of BDNF can be measured. Validating this hypothesis may shed light on the central pathogenic mechanism of ASD and aid in the identification of useful biomarkers and the development of preventive/therapeutic strategies.
机译：尽管异常的大脑连通性可能是自闭症谱系障碍（ASD）的核心病理学，但关于连通性低下还是过度连通性是主要的根本问题，研究并不一致。最近的功能成像研究表明，在大多数年轻的ASD患者中，大脑皮层区域似乎过度连接，并且皮层厚度/大脑大小增加。总的来说，这些发现表明发育中的ASD大脑可能存在于神经营养不良环境中。一致地，一些ASD患者以及一些ASD动物模型显示脑源性神经营养因子（BDNF）水平升高。但是，如何在ASD中上调BDNF尚不清楚。为了解决这个问题，我们提出了一个新的假设，即前脑中假定的锌-金属蛋白酶-BDNF（ZMB）轴在ASD的超连通性和巨脑发育中起着关键作用。先前我们已经证明，微摩尔浓度的细胞外锌可以通过金属蛋白酶的激活快速增加BDNF的水平并磷酸化受体酪氨酸激酶TrkB。金属蛋白酶在ASD中的作用仍不确定，但在脆性X综合征（一种具有自闭表型的单基因疾病）中，MMP的水平会升高。早期暴露于脂多糖（LPS）和其他MMP激活剂（例如有机汞）也与ASD发病机制有关。突触中BDNF水平的升高，尤其是那些与含锌缔合的谷氨酸能系统有关的BDNF升高，可能会导致脑回路发育异常。还已知导致ASD的多种基因突变会影响BDNF信号传导：一些下调，而另一些上调。我们假设，尽管BDNF的上调和下调都可能诱发自闭症症状，但只有BDNF上调与大多数年轻特发性ASD患者中观察到的过度连通性和脑大有关。为了验证该假设，我们建议在ASD动物模型中检查ZMB轴。突触锌可通过荧光锌染色检查。 MMP激活可以通过原位酶谱和Western印迹分析进行测量。最后，可以测量BDNF的区域水平。验证这一假说可以阐明ASD的主要致病机制，并有助于识别有用的生物标志物和制定预防/治疗策略。

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