Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder
Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder
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DOI：
10.1172/jci.insight.131961
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发表时间：
2019-11-01
期刊：
影响因子：
8
通讯作者：
Marsh, Eric D.
中科院分区：
文献类型：
--
作者：
Ahrens-Nicklas, Rebecca C.;Tecedor, Luis;Marsh, Eric D.
溶酶体贮积物质的积累和晚期神经变性是影响大脑的溶酶体贮积症（LSD）的标志。然而，对于大多数LSD，包括CLN 3疾病，最常见的儿童痴呆症形式，目前还不清楚是什么机制驱动神经系统症状。缺陷是由突变蛋白的功能丧失引起的，还是由储存积累引起的毒性引起的？在这里，使用体外电压敏感染料成像和体内电生理学，我们发现在2个CLN 3疾病小鼠模型中，进行性海马功能障碍发生在显著的溶酶体储存和神经元损失之前。药理学逆转年轻小鼠的溶酶体沉积不能挽救这种回路功能障碍。此外，我们发现CLN 3疾病小鼠失去了新记忆编码的电生理标志物--海马尖波波纹。这一发现也见于阿尔茨海默氏病，表明痴呆症的共同电生理特征的可能性。总的来说，我们的数据描述了对LSD影响中枢神经系统的先前未知的网络水平变化的新见解，并强调了针对早期电路缺陷的新治疗干预的必要性。
Accumulation of lysosomal storage material and late-stage neurodegeneration are hallmarks of lysosomal storage disorders (LSDs) affecting the brain. Yet, for most LSDs, including CLN3 disease, the most common form of childhood dementia, it is unclear what mechanisms drive neurologic symptoms. Do deficits arise from loss of function of the mutated protein or toxicity from storage accumulation? Here, using in vitro voltage-sensitive dye imaging and in vivo electrophysiology, we find progressive hippocampal dysfunction occurs before notable lysosomal storage and neuronal loss in 2 CLN3 disease mouse models. Pharmacologic reversal of lysosomal storage deposition in young mice does not rescue this circuit dysfunction. Additionally, we find that CLN3 disease mice lose an electrophysiologic marker of new memory encoding - hippocampal sharp-wave ripples. This discovery, which is also seen in Alzheimer's disease, suggests the possibility of a shared electrophysiologic signature of dementia. Overall, our data describe new insights into previously unknown network-level changes occurring in LSDs affecting the central nervous system and highlight the need for new therapeutic interventions targeting early circuit defects.