Tahara Mayu, Higurashi Norimichi, Hata Junichi, Nishikawa Masako, Ito Ken, Hirose Shinichi, Kaneko Takehito, Mashimo Tomoji, Sakuma Tetsushi, Yamamoto Takashi, Okano Hirotaka James
Department of Pediatrics, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
Division of Regenerative Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
Front Neurol. 2023 Mar 14;14:1125089. doi: 10.3389/fneur.2023.1125089. eCollection 2023.
Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy characterized by an age-dependent evolution of drug-resistant seizures and poor developmental outcomes. Functional impairment of gamma-aminobutyric acid (GABA)ergic interneurons due to loss-of-function mutation of is currently considered the main pathogenesis. In this study, to better understand the age-dependent changes in the pathogenesis of DS, we characterized the activity of different brain regions in knockout rats at each developmental stage.
We established an knockout rat model and examined brain activity from postnatal day (P) 15 to 38 using a manganese-enhanced magnetic resonance imaging technique (MEMRI).
heterozygous knockout (1 ) rats showed a reduced expression of voltage-gated sodium channel alpha subunit 1 protein in the brain and heat-induced seizures. Neural activity was significantly higher in widespread brain regions of 1 rats than in wild-type rats from P19 to P22, but this difference did not persist thereafter. Bumetanide, a Na-K-2Cl cotransporter 1 inhibitor, mitigated hyperactivity to the wild-type level, although no change was observed in the fourth postnatal week. Bumetanide also increased heat-induced seizure thresholds of 1 rats at P21.
In 1 rats, neural activity in widespread brain regions increased during the third postnatal week, corresponding to approximately 6 months of age in humans, when seizures most commonly develop in DS. In addition to impairment of GABAergic interneurons, the effects of bumetanide suggest a possible contribution of immature type A gamma-aminobutyric acid receptor signaling to transient hyperactivity and seizure susceptibility during the early stage of DS. This hypothesis should be addressed in the future. MEMRI is a potential technique for visualizing changes in basal brain activity in developmental and epileptic encephalopathies.
德雷维特综合征（DS）是一种婴儿期起病的发育性和癫痫性脑病，其特征为耐药性癫痫发作随年龄演变以及发育结局不佳。目前认为，由于功能丧失突变导致的γ-氨基丁酸（GABA）能中间神经元功能障碍是主要发病机制。在本研究中，为了更好地理解DS发病机制中的年龄依赖性变化，我们对每个发育阶段的敲除大鼠不同脑区的活动进行了特征描述。
我们建立了敲除大鼠模型，并使用锰增强磁共振成像技术（MEMRI）从出生后第15天（P）至38天检测脑活动。
杂合敲除（1）大鼠脑内电压门控钠通道α亚基1蛋白表达降低且出现热诱导癫痫发作。从P19至P22，1大鼠广泛脑区的神经活动显著高于野生型大鼠，但此后这种差异不再持续。布美他尼，一种钠-钾-2氯协同转运蛋白1抑制剂，将多动减轻至野生型水平，尽管在出生后第四周未观察到变化。布美他尼还提高了P21时1大鼠的热诱导癫痫阈值。
在1大鼠中，广泛脑区的神经活动在出生后第三周增加，这相当于人类约6个月大时，而这正是DS中癫痫最常发生的时期。除了GABA能中间神经元受损外，布美他尼的作用表明未成熟的A型γ-氨基丁酸受体信号可能在DS早期对短暂多动和癫痫易感性有贡献。这一假说有待未来进一步研究。MEMRI是一种可视化发育性和癫痫性脑病基础脑活动变化的潜在技术。
