Marks Wendie N, Zabder Nadine K, Cain Stuart M, Snutch Terrance P, Howland John G
University of Saskatchewan, Department of Physiology, Saskatoon, SK, Canada.
University of Saskatchewan, Department of Physiology, Saskatoon, SK, Canada.
Behav Brain Res. 2019 Apr 1;361:54-64. doi: 10.1016/j.bbr.2018.12.021. Epub 2018 Dec 11.
Abnormalities in social behavior are a co-morbid symptom of idiopathic generalized epilepsies such as childhood absence epilepsy. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model is a spontaneously occurring absence epilepsy phenotype closely correlated to that of human absence epilepsies. Similar to the human conditions, GAERS display social abnormalities. Previous studies have only demonstrated social abnormalities in female GAERS, whereas social problems are observed in male and female patients. Seizures in GAERS result in part due to a gain-of-function missense mutation in the Cav3.2 T-type calcium channel gene. This study examined the effects of the pan-T-type calcium channel antagonist, Z944, on social interaction behaviors in male and female GAERS using an open field social interaction test. A second objective of this study was to examine the effects of Z944 on anxiety-like behavior in an open field locomotion test and elevated plus maze. Results showed a decrease in social activity in GAERS relative to non-epileptic control (NEC) rats. Acute, systemic Z944 (5 mg/kg; i.p.) consistently reduced introductory and aggressive behaviors in both GAERS and NECs whereas strain effects were observed for over-and-under crawl behaviors. In the open field locomotion test and elevated plus maze, Z944 increased anxiety-like behaviors in GAERS, whereas, Z944 produced inconsistent effects on anxiety-like behaviors in NECs. The results of this study suggest that the regulation of T-type calcium channel activity may be a useful strategy for the development of new therapeutic approaches for the treatment of social and affective abnormalities observed in absence epilepsy disorders.
社会行为异常是特发性全身性癫痫（如儿童失神癫痫）的一种共病症状。来自斯特拉斯堡的遗传性失神癫痫大鼠（GAERS）模型是一种自发出现的失神癫痫表型，与人类失神癫痫密切相关。与人类情况相似，GAERS表现出社会行为异常。先前的研究仅在雌性GAERS中证明了社会行为异常，而在男性和女性患者中均观察到社会问题。GAERS的癫痫发作部分是由于Cav3.2 T型钙通道基因的功能获得性错义突变所致。本研究使用旷场社交互动试验，研究了泛T型钙通道拮抗剂Z944对雄性和雌性GAERS社交互动行为的影响。本研究的第二个目的是在旷场运动试验和高架十字迷宫试验中研究Z944对焦虑样行为的影响。结果显示，与非癫痫对照（NEC）大鼠相比，GAERS的社交活动减少。急性全身性给予Z944（5mg/kg；腹腔注射）持续降低GAERS和NEC的初次接触和攻击行为，而对于上爬和下爬行为则观察到品系效应。在旷场运动试验和高架十字迷宫试验中，Z944增加了GAERS的焦虑样行为，而Z944对NEC的焦虑样行为产生的影响不一致。本研究结果表明，调节T型钙通道活性可能是开发新治疗方法的有用策略，用于治疗失神癫痫障碍中观察到的社会和情感异常。
