Department of Physiology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Neurobiol Dis. 2016 Oct;94:106-15. doi: 10.1016/j.nbd.2016.06.001. Epub 2016 Jun 6.
Childhood absence epilepsy (CAE) is often comorbid with behavioral and cognitive symptoms, including impaired visual memory. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is an animal model closely resembling CAE; however, cognition in GAERS is poorly understood. Crossmodal object recognition (CMOR) is a recently developed memory task that examines not only purely visual and tactile memory, but also requires rodents to integrate sensory information about objects gained from tactile exploration to enable visual recognition. Both the visual and crossmodal variations of the CMOR task rely on the perirhinal cortex, an area with dense expression of T-type calcium channels. GAERS express a gain-in-function missense mutation in the Cav3.2 T-type calcium channel gene. Therefore, we tested whether the T-type calcium channel blocker Z944 dose dependently (1, 3, 10mg/kg; i.p.) altered CMOR memory in GAERS compared to the non-epileptic control (NEC) strain. GAERS demonstrated recognition memory deficits in the visual and crossmodal variations of the CMOR task that were reversed by the highest dose of Z944. Electroencephalogram recordings determined that deficits in CMOR memory in GAERS were not the result of seizures during task performance. In contrast, NEC showed a decrease in CMOR memory following Z944 treatment. These findings suggest that T-type calcium channels mediate CMOR in both the GAERS and NEC strains. Future research into the therapeutic potential of T-type calcium channel regulation may be particularly fruitful for the treatment of CAE and other disorders characterized by visual memory deficits.
儿童失神癫痫（CAE）常伴有行为和认知症状，包括视觉记忆受损。斯特拉斯堡遗传性失神癫痫大鼠（GAERS）是一种与 CAE 非常相似的动物模型；然而，GAERS 的认知功能仍不清楚。跨模态物体识别（CMOR）是一种新开发的记忆任务，不仅检查纯粹的视觉和触觉记忆，还要求啮齿动物整合通过触觉探索获得的有关物体的感觉信息，以便进行视觉识别。CMOR 任务的视觉和跨模态变化都依赖于具有密集 T 型钙通道表达的边缘下皮层。GAERS 在 Cav3.2 T 型钙通道基因中表达功能获得性错义突变。因此，我们测试了 T 型钙通道阻滞剂 Z944 是否以剂量依赖性方式（1、3、10mg/kg；ip）改变 GAERS 与非癫痫对照（NEC）品系之间的 CMOR 记忆。GAERS 在 CMOR 任务的视觉和跨模态变化中表现出记忆缺陷，而最高剂量的 Z944 可逆转这种缺陷。脑电图记录确定，GAERS 中 CMOR 记忆缺陷不是任务执行过程中癫痫发作的结果。相比之下，NEC 在 Z944 治疗后 CMOR 记忆下降。这些发现表明 T 型钙通道介导了 GAERS 和 NEC 品系的 CMOR。未来对 T 型钙通道调节治疗潜力的研究可能对治疗 CAE 和其他以视觉记忆缺陷为特征的疾病特别有成效。
