Paradoxical Hyperexcitability in Disorders of Neurodevelopment.
Paradoxical Hyperexcitability in Disorders of Neurodevelopment.
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DOI：
10.3389/fnmol.2022.826679
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发表时间：
2022
影响因子：
4.8
通讯作者：
Antoine, Michelle W.
中科院分区：
文献类型：
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作者：
Antoine, Michelle W.
自闭症谱系障碍（ASD）、Rett综合征（RTT）和Angelman综合征（AS）是神经发育障碍（NDD），具有几个共同的临床特征，包括重复运动、发育迟缓、语言缺陷、智力残疾和癫痫易感性增加。虽然一些评论解决了非癫痫发作相关的ASD表型的生物学基础，在这里，我强调一些共同的生物学机制，可能有助于增加癫痫发作的易感性。我专注于遗传学研究，确定癫痫发作表型的解剖学起源的功能丧失，单基因，这些NDD的小鼠模型，结合从互补的研究中获得的见解量化水平的突触兴奋和抑制。癫痫的特征在于神经元网络内同步活动的突然异常增加，这被认为是由过度兴奋引起的，主要由突触抑制减少驱动。由于这个原因，提出了升高的网络兴奋性作为ASD、RTT和AS表型的因果基础。虽然，这些疾病的小鼠模型复制了人类状况的各个方面，即，在皮层脑电图上，过度兴奋性放电或癫痫发作，在突触水平上的测量通常显示兴奋性突触传递的缺陷，而不是过度兴奋。解决这一明显的悖论对操纵GABA能紧张的预期结果有直接影响。特别是，在与癫痫发作相关的NDD中，皮质回路可以显示降低的而不是正常或增加的突触兴奋水平，因此建议旨在增加抑制的治疗可以进一步促进活动减退而不是正常。在这篇综述中，我强调了ASD，RTT和AS动物模型的共同机制，减少突触兴奋，但促进皮层回路的过度兴奋。
Autism Spectrum Disorder (ASD), Rett syndrome (RTT) and Angelman Syndrome (AS) are neurodevelopmental disorders (NDDs) that share several clinical characteristics, including displays of repetitive movements, developmental delays, language deficits, intellectual disability, and increased susceptibility to epilepsy. While several reviews address the biological basis of non-seizure-related ASD phenotypes, here, I highlight some shared biological mechanisms that may contribute to increased seizure susceptibility. I focus on genetic studies identifying the anatomical origin of the seizure phenotype in loss-of-function, monogenic, mouse models of these NDDs, combined with insights gained from complementary studies quantifying levels of synaptic excitation and inhibition. Epilepsy is characterized by a sudden, abnormal increase in synchronous activity within neuronal networks, that is posited to arise from excess excitation, largely driven by reduced synaptic inhibition. Primarily for this reason, elevated network excitability is proposed to underlie the causal basis for the ASD, RTT, and AS phenotypes. Although, mouse models of these disorders replicate aspects of the human condition, i.e., hyperexcitability discharges or seizures on cortical electroencephalograms, measures at the synaptic level often reveal deficits in excitatory synaptic transmission, rather than too much excitation. Resolving this apparent paradox has direct implications regarding expected outcomes of manipulating GABAergic tone. In particular, in NDDs associated with seizures, cortical circuits can display reduced, rather than normal or increased levels of synaptic excitation, and therefore suggested treatments aimed at increasing inhibition could further promote hypoactivity instead of normality. In this review, I highlight shared mechanisms across animal models for ASD, RTT, and AS with reduced synaptic excitation that nevertheless promote hyperexcitability in cortical circuits.
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