Stafstrom Carl E, Shao Li-Rong
Division of Pediatric Neurology, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Children (Basel). 2024 Dec 13;11(12):1513. doi: 10.3390/children11121513.
Infantile spasms are common in Down Syndrome (DS), but the mechanisms by which DS predisposes to this devastating epilepsy syndrome are unclear. In general, neuronal excitability and therefore seizure predisposition results from an imbalance of excitation over inhibition in neurons and neural networks of the brain. Animal models provide clues to mechanisms and thereby provide potential therapeutic approaches. Ts65Dn mice have been the most widely used animal model of DS. In this model, there is evidence for both abnormal cerebral excitation and inhibition: infantile spasms-like clinical and electrographic activity can be elicited by the administration of gamma-aminobutyric acid (GABA)-B receptor agonist, gamma-butyrolactone (GBL), and depolarizing GABA-A responses persist beyond the age of their usual switch to hyperpolarized responses. But despite its widespread use, the Ts65Dn model may be suboptimal because of the absence of numerous genes that are triplicated in human DS and the presence of numerous genes that are not triplicated in human DS. Recently, a transchromosomic mouse artificial chromosome 21 (TcMAC21) mouse model has been developed, which carries a copy of human chromosome 21 and therefore has a genetic composition more similar to human DS. As in Ts65Dn mice, exposure of TcMAC21 mice to GBL results in epileptic spasms, and aberrant excitation has also been demonstrated. This review summarizes excitatory and inhibitory dysfunction in models of DS that may play a role in the generation of seizures and infantile spasms, providing a perspective on past studies and a prelude for future ones. Further elucidation will hopefully lead to rational therapeutic options for DS children with infantile spasms.
婴儿痉挛症在唐氏综合征（DS）中很常见，但DS易患这种毁灭性癫痫综合征的机制尚不清楚。一般来说，神经元兴奋性以及因此导致的癫痫易感性是由大脑神经元和神经网络中兴奋与抑制的失衡引起的。动物模型为机制提供了线索，从而提供了潜在的治疗方法。Ts65Dn小鼠一直是使用最广泛的DS动物模型。在这个模型中，有证据表明大脑存在异常的兴奋和抑制：给予γ-氨基丁酸（GABA）-B受体激动剂γ-丁内酯（GBL）可引发类似婴儿痉挛症的临床和脑电图活动，并且去极化的GABA-A反应在其通常转变为超极化反应的年龄之后仍然持续。但是，尽管它被广泛使用，Ts65Dn模型可能并不理想，因为它缺乏在人类DS中三倍体化的众多基因，并且存在在人类DS中没有三倍体化的众多基因。最近，一种携带人类21号染色体拷贝的转染色体小鼠人工染色体21（TcMAC21）小鼠模型已经被开发出来，因此其基因组成与人类DS更相似。与Ts65Dn小鼠一样，将TcMAC21小鼠暴露于GBL会导致癫痫性痉挛，并且也已经证明存在异常兴奋。这篇综述总结了DS模型中可能在癫痫发作和婴儿痉挛症产生中起作用的兴奋性和抑制性功能障碍，为过去的研究提供了一个视角，并为未来的研究做了铺垫。希望进一步的阐明能够为患有婴儿痉挛症的DS儿童带来合理的治疗选择。
