Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation.
Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation.
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DOI：
10.1186/s12974-015-0262-3
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发表时间：
2015-03-25
影响因子：
9.3
通讯作者：
Wenk GL
中科院分区：
文献类型：
--
作者：
Hopp SC;D'Angelo HM;Royer SE;Kaercher RM;Crockett AM;Adzovic L;Wenk GL
慢性神经炎症和钙（Ca+2）失调都是阿尔茨海默病的组成部分。长期的神经炎症引起促炎细胞因子和活性氧的升高，其可以通过L型电压依赖性Ca+2通道（L-VDCCs）和兰尼碱受体（RyRs）改变神经元Ca+2稳态。慢性神经炎症还导致空间记忆的缺陷，这可能与Ca+2失调有关。本文中的研究使用慢性神经炎症的体内模型：向大鼠脑室内输注连续小剂量的脂多糖（LPS）或人工脑脊液（aCSF）28天。用L-VDCC拮抗剂尼莫地平或RyR拮抗剂丹曲林治疗大鼠。LPS灌注大鼠在Morris水迷宫中有明显的记忆缺陷，尼莫地平治疗可改善这种缺陷。LPS灌注大鼠的突触体增加了Ca+2的摄取，这是通过在体内或离体阻断L-VDCCs而减少的。总之，这些数据表明，慢性神经炎症期间Ca+2失调部分依赖于L-VDCC功能的增加。然而，RyR的阻断也略微改善了LPS灌注大鼠的空间记忆，表明其他Ca+2通道在慢性神经炎症期间失调。在用丹曲林或尼莫地平治疗的LPS输注大鼠中，Ca+2依赖性立即早期基因表达减少，表明正常化的突触功能可能是空间记忆改善的基础。在用任一种药物治疗的LPS输注大鼠中，促炎标记物也减少。总体而言，这些数据表明，Ca+2失调通过L-VDCCs和RyR发挥了至关重要的作用，在记忆缺陷造成的慢性神经炎症。
Chronic neuroinflammation and calcium (Ca+2) dysregulation are both components of Alzheimer’s disease. Prolonged neuroinflammation produces elevation of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal Ca+2 homeostasis via L-type voltage-dependent Ca+2 channels (L-VDCCs) and ryanodine receptors (RyRs). Chronic neuroinflammation also leads to deficits in spatial memory, which may be related to Ca+2 dysregulation. The studies herein use an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days. The rats were treated with the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. LPS-infused rats had significant memory deficits in the Morris water maze, and this deficit was ameliorated by treatment with nimodipine. Synaptosomes from LPS-infused rats had increased Ca+2 uptake, which was reduced by a blockade of L-VDCCs either in vivo or ex vivo. Taken together, these data indicate that Ca+2 dysregulation during chronic neuroinflammation is partially dependent on increases in L-VDCC function. However, blockade of the RyRs also slightly improved spatial memory of the LPS-infused rats, demonstrating that other Ca+2 channels are dysregulated during chronic neuroinflammation. Ca+2-dependent immediate early gene expression was reduced in LPS-infused rats treated with dantrolene or nimodipine, indicating normalized synaptic function that may underlie improvements in spatial memory. Pro-inflammatory markers are also reduced in LPS-infused rats treated with either drug. Overall, these data suggest that Ca+2 dysregulation via L-VDCCs and RyRs play a crucial role in memory deficits resulting from chronic neuroinflammation.
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影响因子：
16.2
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
Hauss-Wegrzyniak, B;Vraniak, PD;Wenk, GL
通讯作者：
Wenk, GL