PDF(Pubmed)
Abstract：
Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ~6-7 months and ~12 months of age, malin deficient mice (\"KO\") and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using an in vitro assay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.
摘要：
Lafora病（LD）是由EPM2A（laforin）或NHLRC1（malin）的隐性遗传遗传损伤引起的进行性肌阵挛性癫痫和累积性神经认知恶化的综合征。LD中的神经精神症状被认为是神经元和星形细胞聚葡聚糖聚集体的直接下游，称为拉福拉机构(LBs)，在LD的所有小鼠模型中以年龄依赖性的方式忠实地积累。在这项研究中,我们应用家庭笼监测来检查神经行为恶化的程度在一个模型的malin缺乏LD，作为确定可靠的临床前终点的手段，可以指导选择新的基因治疗。在6周,6-7个月和12个月的年龄，malin缺陷小鼠（“KO”）和野生型（WT）同窝进行了标准化的家庭笼子行为评估，旨在非突发性地评估休息/唤醒的特征，消费行为，风险规避和自愿车轮运行。在所有时间点，在我们透明报告的一系列指标上，WT和KO小鼠基本上无法区分。相比之下,在WT小鼠中，跨时间点进行比较，我们发现了与年龄相关的夜间活动不足，蔗糖偏好减少，车轮运行减少。相同小鼠亚群的神经病理学检查显示预期的年龄依赖性LB积累，皮质和皮质下脑区域的胶质增生和小胶质细胞活化。在12个月大的时候，尽管有新皮质LBs的负担，我们在脑电图（EEG）调查中没有发现自发性癫痫发作，KO和WT小鼠表现出相似的频谱脑电图特征。使用新皮层功能的体外测定，KO切片中网络活动的阵发性增加（UP状态）在3个月和6个月大时延长，但在12个月时与WT相似。KO小鼠对戊四唑表现出明显的反应，阵挛性癫痫发作的发生率更高，发作后运动抑制更明显，喂养和饮酒行为。一起,这些结果突出了LD小鼠模型的明显临床病理分离，LBs的积累基本上没有临床意义的整体健康变化。我们的发现暗示了LB积累和神经行为下降之间的延迟：这可能为治疗提供了一个窗口，在实验室老鼠的典型寿命内，其确切持续时间可能很难确定。
