Increased hippocampal excitability in the 3xTgAD mouse model for Alzheimer's disease in vivo.
Increased hippocampal excitability in the 3xTgAD mouse model for Alzheimer's disease in vivo.
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DOI：
10.1371/journal.pone.0091203
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gigg J
中科院分区：
文献类型：
--
作者：
Davis KE;Fox S;Gigg J
小鼠阿尔茨海默病（AD）模型在整个海马形成中发展出年龄和区域特异性病理。最近建立的一种病理关联是体内海马兴奋性的增加。海马病理也会导致人类AD的情景记忆下降，我们已经在3-6个月大的3xTg AD模型小鼠中发现了类似的情景缺失。在这里，我们通过探测麻醉4-6月龄3xTgAD小鼠的背侧CA1和DG突触反应来测试海马突触功能障碍是否伴随这种认知缺陷。由于我们之前的报告强调了老年对照小鼠发作性表现的下降，我们纳入了老年队列进行比较。在这两个年龄段，3xTgAD和对照组对低频射孔路径刺激的CA1和DG反应是相似的。正如预期的那样，对照组的DG记录显示成对脉冲抑制；然而，青年和老年3xTgAD小鼠的DG和CA1均出现配对脉冲促进。在刺激训练中，观察到短潜伏期（可能是单突触：“直接”）和长潜伏期（可能是多突触：“重新进入”）反应。在3xTgAD动物中，直接反应的促进作用不大。然而，与对照组相比，年轻3xTgAD小鼠的DG和CA1的再入反应在刺激序列中出现得更早，幅度更大。老龄小鼠DG配对脉冲抑制较少，无再入迹象。综上所述，DG和CA1对低频刺激的反应在所有组中都是相似的，这表明3xTgAD小鼠的突触连通性没有丧失。然而，高频激活揭示了3xTgAD小鼠DG和CA1突触兴奋性的复杂变化。特别是，3xTgAD小鼠促进了DG和CA1的短期可塑性，在年轻动物中最为明显。此外，年轻的3xTgAD小鼠也容易重新进入。总的来说，这些数据表明，3xTgAD小鼠的情景样记忆缺陷可能是由于海马形成异常的超兴奋状态的发展。
Mouse Alzheimer's disease (AD) models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3–6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4–6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: ‘direct’) and long-latency (presumably polysynaptic: ‘re-entrant’) responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice could be due to the development of an abnormal hyper-excitable state in the hippocampal formation.
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