Becchetti Andrea, Grandi Laura Clara, Cerina Marta, Amadeo Alida
Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy.
Department of Biosciences, University of Milano, Via Celoria 26, Milano 20133, Italy.
Pharmacol Res. 2023 Mar;189:106698. doi: 10.1016/j.phrs.2023.106698. Epub 2023 Feb 14.
Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype remains difficult. A paradigmatic case is constituted by the epilepsies caused by altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions in mature as well as developing brain. The ascending cholinergic projections exert potent control of forebrain excitability, and wide evidence implicates nAChR dysregulation as both cause and effect of epileptiform activity. First, tonic-clonic seizures are triggered by administration of high doses of nicotinic agonists, whereas non-convulsive doses have kindling effects. Second, sleep-related epilepsy can be caused by mutations on genes encoding nAChR subunits widely expressed in the forebrain (CHRNA4, CHRNB2, CHRNA2). Third, in animal models of acquired epilepsy, complex time-dependent alterations in cholinergic innervation are observed following repeated seizures. Heteromeric nAChRs are central players in epileptogenesis. Evidence is wide for autosomal dominant sleep-related hypermotor epilepsy (ADSHE). Studies of ADSHE-linked nAChR subunits in expression systems suggest that the epileptogenic process is promoted by overactive receptors. Investigation in animal models of ADSHE indicates that expression of mutant nAChRs can lead to lifelong hyperexcitability by altering i) the function of GABAergic populations in the mature neocortex and thalamus, ii) synaptic architecture during synaptogenesis. Understanding the balance of the epileptogenic effects in adult and developing networks is essential to plan rational therapy at different ages. Combining this knowledge with a deeper understanding of the functional and pharmacological properties of individual mutations will advance precision and personalized medicine in nAChR-dependent epilepsy.
尽管最近在理解癫痫病因方面取得了进展，尤其是在遗传学方面，但要理解导致癫痫表型的生物学机制仍然很困难。一个典型的例子是由神经元烟碱型乙酰胆碱受体（nAChRs）改变引起的癫痫，这些受体在成熟和发育中的大脑中发挥着复杂的生理功能。上行胆碱能投射对前脑兴奋性有强大的控制作用，大量证据表明nAChR失调既是癫痫样活动的原因也是结果。首先，高剂量烟碱激动剂的给药会引发强直阵挛性发作，而非惊厥剂量则有点燃效应。其次，睡眠相关性癫痫可能由在前脑广泛表达的nAChR亚基编码基因（CHRNA4、CHRNB2、CHRNA2）的突变引起。第三，在获得性癫痫的动物模型中，反复癫痫发作后观察到胆碱能神经支配存在复杂的时间依赖性改变。异聚体nAChRs是癫痫发生的核心因素。常染色体显性遗传性睡眠相关性运动过多癫痫（ADSHE）有广泛的证据。在表达系统中对与ADSHE相关的nAChR亚基的研究表明，癫痫发生过程是由过度活跃的受体促进的。对ADSHE动物模型的研究表明，突变型nAChRs的表达可通过改变以下方面导致终身性兴奋性过高：i）成熟新皮层和丘脑中GABA能神经元群的功能，ii）突触形成过程中的突触结构。了解成人和发育中神经网络中癫痫发生效应的平衡对于制定不同年龄段的合理治疗方案至关重要。将这些知识与对个体突变的功能和药理学特性的更深入理解相结合，将推动nAChR依赖性癫痫的精准和个性化医学发展。
