Loss of presenilin 2 age-dependently alters susceptibility to acute seizures and kindling acquisition
Loss of presenilin 2 age-dependently alters susceptibility to acute seizures and kindling acquisition
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DOI：
10.1016/j.nbd.2019.104719
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发表时间：
2020-03-01
影响因子：
6.1
通讯作者：
Barker-Haliski, Melissa
中科院分区：
文献类型：
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作者：
Beckman, Megan;Knox, Kevin;Barker-Haliski, Melissa
阿尔茨海默病（AD）患者的癫痫发作率高于同龄人群，这表明过度兴奋性在AD中的作用尚未得到充分研究。早老素（PSEN） 1和2基因的遗传变异导致常染色体显性早发型AD (ADAD)；PSEN基因变异的患者也报告癫痫发作。阿尔茨海默病癫痫发作的药物控制可能对疾病有改善作用。fda批准的抗癫痫药物（ASDs）在年轻成年啮齿动物中的临床前疗效明确；然而，自闭症谱系障碍对老年啮齿动物慢性癫痫发作的疗效尚不清楚。ADAD基因导致AD的机制尚不清楚，对AD患者癫痫的发病机制研究更少。PSEN变异通常都会导致功能的生化丧失（De Strooper, 2007）。我们在此通过研究正常PSEN2功能的丧失是否会影响癫痫发作和/或角膜点燃获得的易感性，来确定建立的急性和慢性癫痫发作模型是否可以用于探索AD基因与癫痫发作之间的关系。筛选PSEN2敲除（KO）和年龄匹配的野生型（WT）小鼠，从2至10个月大建立年龄依赖性局灶性癫痫阈值。此外，2个月和8个月大的PSEN2 KO和WT小鼠进行角膜点火，使小鼠在3个月和9个月大时开始进行ASD功效测试。然后，我们定义了机制不同的asd对年轻小鼠和老年小鼠点燃癫痫发作的剂量依赖性疗效，以更好地了解角膜点燃在老年患者的实际应用中的适用性。PSEN2 KO小鼠表现出早期发作阈值的降低。然而，在2个月大的PSEN2 KO小鼠中，与WT小鼠相比，点燃获得延迟。年轻雄性WT小鼠需要24.3 +/- 1.3 （S.E.M.）刺激才能达到点火标准，而年龄匹配的PSEN2 KO雄性小鼠需要41.2 +/- 1.1刺激（p < 0.0001）。8个月大小鼠的点火获得率不再与WT不同。本研究表明，正常PSEN2功能的丧失与体内急性发作和点火易感性的年龄依赖性变化有关。正常PSEN2功能的丧失可能是癫痫发作的一个未被充分探索的分子因素。使用老年啮齿动物慢性癫痫发作的验证模型可能揭示AD相关基因型小鼠癫痫发生易感性和/或ASD疗效的年龄相关变化，这可能有利于AD发作的管理。
Patients with Alzheimer's disease (AD) experience seizures at higher rates than the general population of that age, suggesting an underexplored role of hyperexcitability in AD. Genetic variants in presenilin (PSEN) 1 and 2 genes lead to autosomal dominant early-onset AD (ADAD); patients with PSEN gene variants also report seizures. Pharmacological control of seizures in AD may be disease-modifying. Preclinical efficacy of FDA-approved antiseizure drugs (ASDs) is well defined in young adult rodents; however, the efficacy of ASDs in aged rodents with chronic seizures is less clear. The mechanism by which ADAD genes lead to AD remains unclear, and even less studied is the pathogenesis of epilepsy in AD. PSEN variants generally all result in a biochemical loss of function (De Strooper, 2007). We herein determined whether well-established models of acute and chronic seizure could be used to explore the relationship between AD genes and seizures through investigating whether loss of normal PSEN2 function age-dependently influenced susceptibility to seizures and/or corneal kindling acquisition. PSEN2 knockout (KO) and age-matched wild-type (WT) mice were screened from 2- to 10-months-old to establish age-dependent focal seizure threshold. Additionally, PSEN2 KO and WT mice aged 2- and 8-months-old underwent corneal kindling such that mice were aged 3- and 9-months old at the beginning of ASD efficacy testing. We then defined the dose-dependent efficacy of mechanistically distinct ASDs on kindled seizures of young versus aged mice to better understand the applicability of corneal kindling to real-world use for geriatric patients. PSEN2 KO mice demonstrated early-life reductions in seizure threshold. However, kindling acquisition was delayed in 2-month-old PSEN2 KO versus WT mice. Young male WT mice took 24.3 +/- 1.3 (S.E.M.) stimulations to achieve kindling criterion, whereas age-matched PSEN2 KO male mice took 41.2 +/- 1.1 stimulations (p < .0001). The rate of kindling acquisition of 8-month-old mice was no longer different from WT. This study demonstrates that loss of normal PSEN2 function is associated with age-dependent changes in the in vivo susceptibility to acute seizures and kindling. Loss of normal PSEN2 function may be an underexplored molecular contributor to seizures. The use of validated models of chronic seizures in aged rodents may uncover age-related changes in susceptibility to epileptogenesis and/or ASD efficacy in mice with AD-associated genotypes, which may benefit the management of seizures in AD.