Altered cortical glutamate receptor function in the r6/2 model of Huntington's disease
Altered cortical glutamate receptor function in the r6/2 model of Huntington's disease
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DOI：
10.1152/jn.01118.2005
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发表时间：
2006-04-01
影响因子：
2.5
通讯作者：
Levine, MS
中科院分区：
文献类型：
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作者：
André, VM;Cepeda, C;Levine, MS
感觉运动皮层锥体神经元的改变可能是亨廷顿病 (HD) 的一些认知和运动症状的原因。本实验使用 R6/2 转基因小鼠，其表达人类 HD 基因的外显子 1，并具有更多的 CAG 重复序列。我们表征了 R6/2 转基因和野生型 (WT) 小鼠在 21 天（出现明显症状之前）、40 天（出现症状时）急性分离皮质锥体神经元中的 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 电流及其受环噻嗪 (CTZ) 的调节以及 N-甲基-D-天冬氨酸 (NMDA) 电流及其 Mg(2+) 敏感性。开始）和 80 天（完全有症状）。与 WT 小鼠相比，21 日龄和 40 日龄 R6/2 组的 AMPA 电流（单独使用或 CTZ 存在时）较小。在 R6/2 小鼠中，更多的神经元在 CTZ 存在的情况下表现出脱敏 AMPA 电流，表明“翻转”剪接变体的表达增加，而大多数 WT 细胞表达 AMPA 受体亚基的“翻转”变体。第 21 天时，R6/2 锥体神经元的 NMDA 峰值电流也较小。 40 天时，WT 和 R6/2 小鼠的 NMDA 电流相似，但 R6/2 小鼠对 Mg(2+) 的敏感性更高，导致 Mg(2+) 存在时 NMDA 电流更小。 80 天时不再检测到 WT 和 R6/2 细胞之间 AMPA 和 NMDA 电流的差异。我们的研究结果表明，在 R6/2 小鼠分离的皮质锥体神经元中，谷氨酸受体激动剂诱导的电流减少，并且这种减少发生得很早。谷氨酸受体功能的改变可能导致皮质输出的变化，并且可能是这种 HD 动物模型中一些认知和运动障碍的基础。
Alterations in pyramidal neurons from the sensorimotor cortex may be responsible for some of the cognitive and motor symptoms of Huntington's disease (HD). The present experiments used R6/2 transgenic mice that express exon 1 of the human HD gene with an expanded number of CAG repeats. We characterized alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( AMPA) currents and their modulation by cyclothiazide (CTZ) as well as N-methyl-D-aspartate ( NMDA) currents and their Mg(2+) sensitivity in acutely dissociated cortical pyramidal neurons in R6/2 transgenic and wild-type (WT) mice at 21 days ( before overt symptoms), 40 days ( when symptoms begin), and 80 days ( fully symptomatic). AMPA currents, alone or in the presence of CTZ, were smaller in 21- and 40-day-old R6/2 groups compared with WT mice. In R6/2 mice, more neurons displayed desensitizing AMPA currents in the presence of CTZ, indicating increased expression of "flop" splice variants, whereas the majority of WT cells expressed the "flip" variants of AMPA receptor subunits. NMDA peak currents also were smaller in R6/2 pyramidal neurons at 21 days. At 40 days, NMDA currents were similar in WT and R6/2 mice but Mg(2+) sensitivity was greater in R6/2 mice, resulting in smaller NMDA currents in the presence of Mg(2+). Differences in AMPA and NMDA currents between WT and R6/2 cells were no longer detected at 80 days. Our findings indicate that currents induced by glutamate receptor agonists are decreased in isolated cortical pyramidal neurons from R6/2 mice and that this decrease occurs early. Altered glutamate receptor function could contribute to changes in cortical output and may underlie some of the cognitive and motor impairments in this animal model of HD.