Regulation of neuronal plasticity and fear by a dynamic change in PAR1-G protein coupling in the amygdala
Regulation of neuronal plasticity and fear by a dynamic change in PAR1-G protein coupling in the amygdala
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DOI：
10.1038/mp.2012.133
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发表时间：
2013-10-01
影响因子：
11
通讯作者：
Pawlak, R.
中科院分区：
文献类型：
--
作者：
Bourgognon, J-M;Schiavon, E.;Pawlak, R.
恐惧记忆是通过神经元的可塑性获得的，这是在电路和细胞水平上调节的一系列精心安排的事件。传统的恐惧习得模型假设了调节受体在控制神经元活动和学习中的单峰（例如，兴奋性或抑制性）作用。与这一观点相反，我们发现蛋白酶激活受体-1 （PAR1）通过不同G蛋白偶联伙伴之间的动态转换，根据动物的情绪状态促进不同的神经元反应。在恐惧初始小鼠的基底外侧杏仁核中，PAR1与G α (q/11)和G α (o)蛋白偶联，而在恐惧条件反射后，PAR1与G α (o)蛋白偶联增加。同时，在条件反射前刺激PAR1增强，但在条件反射后抑制基底杏仁核神经元的放电。par1缺陷小鼠的长期增强（LTP）的初始损伤转化为LTP的增加和条件反射后恐惧的增强。这些效应与更频繁的2-氨基-3-（5-甲基-3-氧-1,2-恶唑-4-基）丙酸（AMPA）受体介导的微突触后事件和神经元兴奋性增加有关。我们的研究结果表明，杏仁核中PAR1-G蛋白偶联的经验特异性变化是调节神经元兴奋性和恐惧的新机制。
Fear memories are acquired through neuronal plasticity, an orchestrated sequence of events regulated at circuit and cellular levels. The conventional model of fear acquisition assumes unimodal (for example, excitatory or inhibitory) roles of modulatory receptors in controlling neuronal activity and learning. Contrary to this view, we show that protease-activated receptor-1 (PAR1) promotes contrasting neuronal responses depending on the emotional status of an animal by a dynamic shift between distinct G protein-coupling partners. In the basolateral amygdala of fear-naive mice PAR1 couples to G alpha(q/11) and G alpha(o) proteins, while after fear conditioning coupling to G alpha(o) increases. Concurrently, stimulation of PAR1 before conditioning enhanced, but afterwards it inhibited firing of basal amygdala neurons. An initial impairment of the long-term potentiation (LTP) in PAR1-deficient mice was transformed into an increase in LTP and enhancement of fear after conditioning. These effects correlated with more frequent 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor-mediated miniature post synaptic events and increased neuronal excitability. Our findings point to experience-specific shifts in PAR1-G protein coupling in the amygdala as a novel mechanism regulating neuronal excitability and fear.