Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons.
Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons.
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中脑多巴胺神经元变性后，甲状腺丘脑核核外部核核核的增殖。
DOI：
10.1523/jneurosci.5750-11.2012
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发表时间：
2012-10-03
期刊：
影响因子：
--
通讯作者：
Bevan MD
中科院分区：
文献类型：
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作者：
Fan KY;Baufreton J;Surmeier DJ;Chan CS;Bevan MD
帕金森病 (PD) 的症状与相互连接的 GABA 能外苍白球 (GPe) 和谷氨酸能底丘脑核 (STN) 的活动频率和模式的变化有关。在特发性和实验性 PD 中，GPe 和 STN 分别表现出活动不足和过度活动，以及异常的同步节律爆发。中脑多巴胺神经元损伤后，异常的 STN 活性缓慢出现并逐渐增强，直至 2-3 周后稳定。因此，细胞/网络特性的改变可能是异常放电表达的基础。由于 GPe 强有力地调节 STN 活动的频率、模式和同步性，因此在对照和 6-羟基多巴胺损伤的大鼠和小鼠的 STN 中比较了 GPe-STN 传输的电生理学、分子和解剖学测量。多巴胺耗尽后：1）mIPSC 的频率（但不是幅度）增加约 70%； 2) 诱发的 IPSC 和异鳄梨疫苗诱发的电流的幅度分别增加约 60% 和约 70%； 3）编码α1、β2和γ2 GABAA受体亚基的mRNA增加15-30%； 4) 突触后 gephyrin 和 γ2 亚基共免疫反应结构的密度增加了约 40%，而囊泡 GABA 转运蛋白和巴松管共免疫反应轴突末端的密度没有变化； 5) 每个 GPe-STN 轴突末端超微结构定义的突触数量加倍，但末端/突触大小或目标偏好没有改变。因此，多巴胺的损失通过每个 GPe-STN 轴突末端突触连接数量的增加，导致 GPe-STN 通路的实质性加强。这种适应可能会对抗多动症，但也可能导致帕金森病 STN 的异常放电模式。
The symptoms of Parkinson’s disease (PD) are related to changes in the frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN). In idiopathic and experimental PD the GPe and STN exhibit hypo- and hyper-activity, respectively, and abnormal synchronous rhythmic burst firing. Following lesion of midbrain dopamine neurons abnormal STN activity emerges slowly and intensifies gradually until it stabilizes after 2–3 weeks. Alterations in cellular/network properties may therefore underlie the expression of abnormal firing. Because the GPe powerfully regulates the frequency, pattern and synchronization of STN activity, electrophysiological, molecular and anatomical measures of GPe-STN transmission were compared in the STN of control and 6-hydroxydopamine-lesioned rats and mice. Following dopamine depletion: 1) the frequency (but not the amplitude) of mIPSCs increased by ~70%; 2) the amplitude of evoked IPSCs and isoguvacine-evoked current increased by ~60% and ~70%, respectively; 3) mRNA encoding α1, β2 and γ2 GABAA receptor subunits increased by 15–30%; 4) the density of postsynaptic gephyrin and γ2 subunit co-immunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon co-immunoreactive axon terminals was unchanged; 5) the number of ultrastructurally defined synapses per GPe-STN axon terminal doubled with no alteration in terminal/synapse size or target preference. Thus, loss of dopamine leads, through an increase in the number of synaptic connections per GPe-STN axon terminal, to substantial strengthening of the GPe-STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN.