Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer's disease.
Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer's disease.
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DOI：
10.3233/jad-142427
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Bezprozvanny I
中科院分区：
文献类型：
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作者：
Zhang H;Liu J;Sun S;Pchitskaya E;Popugaeva E;Bezprozvanny I
阿尔茨海默病（AD）和衰老会导致记忆存储能力受损，但造成这些缺陷的细胞机制却知之甚少。早老素 1 (PS1) 突变是许多早发家族性 AD (FAD) 病例的原因。海马长时程增强（LTP）现象广泛应用于记忆形成和存储的研究中。最近的数据显示，PS1-M146V 敲入 (KI) FAD 小鼠的长期 LTP 维持 (L-LTP) 受到损害。为了了解这种现象的基础，在本研究中，我们分析了野生型 (WT) 和 KI 小鼠海马培养物中的结构突触可塑性。我们发现，暴露于印防己毒素 (PTX) 会诱导 WT 和 KI 培养物中蘑菇刺的形成，但 KI 神经元中蘑菇刺的维持受到损害。这种维持缺陷可以通过 KI 神经元结构可塑性巩固阶段的异常放电模式来解释。 KI 神经元中神经元放电频率的降低是由钙诱导钙释放 (CICR) 增强、钙激活钾通道活性增强和后超极化 (AHP) 增加引起的。结果，KI 神经元中神经元活动的“巩固”模式转变为神经元活动的“去潜能”模式。与该模型一致，我们证明 CICR（丹曲林）、钙激活钾通道（apamin）和钙依赖性磷酸酶钙调神经磷酸酶（FK506）的药理学抑制剂能够挽救 KI 神经元的结构可塑性缺陷。此外，我们证明用丹曲林或 apamin 孵育也可以挽救 KI 海马切片中的 L-LTP 缺陷，这表明类似机制的作用。所提出的机制可能是AD记忆缺陷的原因，但也可能是与年龄相关的记忆衰退的原因。
Alzheimer’s disease (AD) and aging result in impaired ability to store memories, but the cellular mechanisms responsible for these defects are poorly understood. Presenilin 1 (PS1) mutations are responsible for many early-onset familial AD (FAD) cases. The phenomenon of hippocampal long-term potentiation (LTP) is widely used in studies of memory formation and storage. Recent data revealed long-term LTP maintenance (L-LTP) is impaired in PS1-M146V knock-in (KI) FAD mice. To understand basis for this phenomenon, in the present study we analyzed structural synaptic plasticity in hippocampal cultures from wild type (WT) and KI mice. We discovered that exposure to picrotoxin (PTX) induces formation of mushroom spines in both WT and KI cultures, but the maintenance of mushroom spines is impaired in KI neurons. This maintenance defect can be explained by abnormal firing pattern during consolidation phase of structural plasticity in KI neurons. Reduced frequency of neuronal firing in KI neurons is caused by enhanced calcium-induced calcium release (CICR), enhanced activity of calcium-activated potassium channels and increased afterhyperpolarization (AHP). As a result, “consolidation” pattern of neuronal activity converted to “depotentiation” pattern of neuronal activity in KI neurons. Consistent with this model we demonstrated that pharmacological inhibitors of CICR (dantrolene), of calcium-activated potassium channels (apamin) and of calcium-dependent phosphatase calcineurin (FK506) are able to rescue structural plasticity defects in KI neurons. Furthermore, we demonstrate that incubation with dantrolene or apamin also rescued L-LTP defects in KI hippocampal slices, suggesting a role for a similar mechanism. Proposed mechanism may be responsible for memory defects in AD but also for age-related memory decline.