Sagol Department of Neurobiology, Faculty of Natural Sciences,, Haifa, Israel.
The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa, Israel.
Sci Rep. 2017 Oct 24;7(1):13930. doi: 10.1038/s41598-017-13674-9.
Fear conditioning, a behavioral model for studying fear-related disorders, is believed to be formed by alterations of synaptic efficacy mediated by changes in synaptic transmission and neuronal morphology in lateral amygdala (LA). Rac GTPase and its downstream effector p21-activated kinase (PAK) are involved in such key neuronal functions. Here we show that optical activation of Rac1 GTPase using photoactivatable form of Rac1 (PA-Rac1) in amygdala led to phosphorylation of PAK and inhibition of long-term but not short-term auditory fear conditioning memory formation. Activation of PA-Rac1 in LA one day after fear conditioning had no effect on long-term fear memory tested 24 hrs after PA-Rac1 activation. Inhibition of PAK in LA by microinjection of the PAK inhibitor IPA-3 30 minutes before fear conditioning enhanced long-term but not short-term fear memory formation. Our results demonstrate that photoactivation of Rac1 GTPase in lateral amygdala impairs fear memory formation. Moreover, Rac1 effector PAK activity during fear conditioning constrains the formation of fear memory in LA. Thus, Rac GTPase and PAK proteins may serve as targets for treatment of fear and anxiety disorders.
恐惧条件反射是一种研究与恐惧相关障碍的行为模型，它被认为是通过改变外侧杏仁核（LA）中的突触传递和神经元形态来介导的突触效能变化而形成的。Rac GTPase 及其下游效应物 p21 激活激酶（PAK）参与了这种关键的神经元功能。在这里，我们显示使用光可激活形式的 Rac1（PA-Rac1）在杏仁核中光激活 Rac1 GTPase 导致 PAK 的磷酸化，并抑制长时但不短时听觉恐惧条件反射记忆的形成。在恐惧条件反射后一天在 LA 中激活 PA-Rac1 对在 PA-Rac1 激活后 24 小时测试的长时恐惧记忆没有影响。在恐惧条件反射前 30 分钟通过微注射 PAK 抑制剂 IPA-3 在 LA 中抑制 PAK 增强了长时但不短时恐惧记忆的形成。我们的结果表明，在外侧杏仁核中光激活 Rac1 GTPase 会损害恐惧记忆的形成。此外，在恐惧条件反射期间 Rac1 效应物 PAK 的活性限制了 LA 中恐惧记忆的形成。因此，Rac GTPase 和 PAK 蛋白可作为治疗恐惧和焦虑障碍的靶标。
