Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
Department of Poisoning and the Treatment, Affiliated Hospital to Academy of Military Medical Sciences (the 307 Hospital), Beijing, China.
Neuropharmacology. 2018 Jan;128:388-400. doi: 10.1016/j.neuropharm.2017.10.037. Epub 2017 Nov 12.
Anxiety disorders represent serious social problems worldwide. Recent neuroimaging studies have found that elevated activity and altered connectivity of the insular cortex might account for the negative emotional states in highly anxious individuals. However, the exact synaptic mechanisms of specific insular subregions have yet to be studied in detail. To assess the electrophysiological properties of agranular insular cortex (AIC) neurons, basic synaptic transmission was recorded and different protocols were used to induce presynaptic and postsynaptic long-term potentiation in mice with anxiety-related behaviors. The presynaptic membrane expression of kainate receptors (KARs) and pharmacologic manipulations were quantified to examine the role of Gluk1 subtype in anxiety-like behaviors. Fear conditioning occludes electrically induced postsynaptic-LTP in the AIC. Quantal analysis of LTP expression in this region revealed a significant presynaptic component reflected by an increase in the probability of transmitter release. A form of presynaptic-LTP that requires KARs has been characterized. Interestingly, a simple emotional anxiety stimulus resulted in selective occlusion of presynaptic-LTP, but not of postsynaptic-LTP. Finally, injecting GluK1-specific antagonists into the AIC reduced behavioral responses to fear or anxiety stimuli in the mouse. These findings suggest that activity-dependent synaptic plasticity takes place in the AIC due to exposure to fear or anxiety, and inhibiting the presynaptic KAR function may help to prevent or treat anxiety disorder.
焦虑障碍是全球范围内严重的社会问题。最近的神经影像学研究发现，脑岛皮层活动增加和连接改变可能是高度焦虑个体出现负面情绪状态的原因。然而，特定脑岛亚区的具体突触机制仍有待详细研究。为了评估无颗粒脑岛皮层（AIC）神经元的电生理特性，记录了基本的突触传递，并在具有焦虑相关行为的小鼠中使用不同的方案诱导突触前和突触后长时程增强。通过量化 kainate 受体（KARs）的突触前膜表达和药理学操作，研究了 Gluk1 亚型在焦虑样行为中的作用。恐惧条件作用会阻断 AIC 中的电诱导突触后-LTP。该区域 LTP 表达的量子分析显示，突触前成分增加，反映出递质释放概率增加。已经描述了一种需要 KAR 的突触前-LTP 形式。有趣的是，简单的情绪性焦虑刺激导致选择性阻断突触前-LTP，但不阻断突触后-LTP。最后，将 GluK1 特异性拮抗剂注入 AIC 可减少小鼠对恐惧或焦虑刺激的行为反应。这些发现表明，由于暴露于恐惧或焦虑，AIC 中会发生依赖于活动的突触可塑性，抑制突触前 KAR 功能可能有助于预防或治疗焦虑障碍。
