Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
Eur J Neurosci. 2019 Sep;50(6):3046-3059. doi: 10.1111/ejn.14406. Epub 2019 Apr 8.
Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are a rodent model of childhood absence epilepsy (CAE) that display a gain-of-function mutation in the gene encoding the Cav3.2 T-type calcium channel. GAERS demonstrate heightened learning and delayed extinction of fear conditioning. Our objective in the present study was to examine the effects of the pan-T-type calcium channel blocker Z944 on the acquisition, consolidation and extinction of conditioned fear in GAERS and the non-epileptic control (NEC) strain. Z944 (10 mg/kg; ip) was administered 15 min prior to either acquisition, extinction day 1 (24 hr later), acquisition and extinction day 1, or during the consolidation (post-acquisition) of tone-cued fear conditioning. Extinction was examined 24 and 48 hr after conditioning. In drug naïve GAERS, increased freezing during the acquisition and extinction phases of fear conditioning was found. Short-term effects of Z944 on performance were observed as Z944 increased freezing during testing on the day it was administered. Z944 administered prior to the acquisition phase had a long-term effect on extinction. Specifically, both GAERS and NECs showed a decrease in freezing during extinction relative to drug naïve GAERS and NEC rats respectively. Regardless of strain or treatment, female rats showed reduced extinction of fear relative to male rats. These results demonstrate that T-type calcium channels contribute to the neural systems that mediate the learning and memory of conditioned fear. Overall, these findings suggest that T-type calcium channel blockers show promise in the treatment of learning impairments observed in disorders such as CAE.
斯特拉斯堡遗传性癫痫大鼠（GAERS）是一种儿童失神癫痫（CAE）的啮齿动物模型，其基因编码 Cav3.2 T 型钙通道存在功能获得性突变。GAERS 表现出增强的学习能力和恐惧条件反射的延迟消退。本研究的目的是研究全 T 型钙通道阻滞剂 Z944 对 GAERS 和非癫痫对照（NEC）品系条件性恐惧获得、巩固和消退的影响。Z944（10mg/kg；ip）在获得前 15 分钟、第 1 天（24 小时后）的消退、获得和消退第 1 天或在音调提示恐惧条件反射的巩固（获得后）期间给予。在条件作用后 24 和 48 小时检查消退。在药物未处理的 GAERS 中，发现恐惧条件反射的获得和消退阶段的冻结增加。Z944 在测试日给药时增加了测试期间的冻结，观察到 Z944 对性能的短期影响。Z944 在获得阶段之前给药对消退有长期影响。具体来说，GAERS 和 NEC 都显示出与药物未处理的 GAERS 和 NEC 大鼠相比，在消退期间冻结减少。无论品系如何或是否接受治疗，雌性大鼠的恐惧消退都比雄性大鼠少。这些结果表明 T 型钙通道有助于介导条件性恐惧的学习和记忆的神经系统。总体而言，这些发现表明 T 型钙通道阻滞剂在治疗 CAE 等疾病中观察到的学习障碍方面具有潜力。
