Department of Neurosurgery, Stanford University, Stanford, California.
Department of Anatomy and Neurobiology, University of California, Irvine, California.
Epilepsia. 2020 Mar;61(3):561-571. doi: 10.1111/epi.16445. Epub 2020 Feb 18.
To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory.
Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed-loop light intervention of seizures. Animals that responded to closed-loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed-loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory.
Animals that received closed-loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult.
Many currently available treatments for epilepsy target seizures but not the associated comorbidities, therefore there is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.
确定闭环光遗传癫痫干预是否能改善慢性颞叶癫痫（TLE）小鼠模型中与癫痫相关的认知障碍，这种干预先前已被证明能缩短癫痫发作持续时间。
在单侧海马内海人酸诱导的 TLE 慢性、自发性癫痫模型中，表达在 parvalbumin 表达中间神经元中的通道视紫红质，对表达通道视紫红质的小鼠进行闭环光干预治疗。对闭环光遗传治疗能减少癫痫发作的动物进行物体位置记忆测试，然后对所有检测到的癫痫发作进行 2 周的闭环光遗传干预。在此之后，对动物进行第二次物体位置记忆测试，使用与之前不同的物体和环境，以评估癫痫发作抑制是否可以改善空间记忆缺陷。
接受闭环光遗传干预的动物在第二次物体位置记忆测试中的表现明显优于第一次测试。未接受干预的癫痫对照组在诱发损伤后几个月内，癫痫发作的频率和持续时间以及空间记忆缺陷均保持稳定。
许多现有的癫痫治疗方法都针对癫痫发作，但不针对与癫痫相关的合并症，因此需要研究新的潜在治疗方法，这些方法可能既能减轻癫痫发作负担，又能改善癫痫的相关合并症。在这项研究中，我们表明光遗传干预可能既能缩短癫痫发作持续时间，又能改善空间记忆的认知结果。
