Impact of stress on GluR2 transcription and learning-induced synaptic plasticity

描述(申请人提供)：小脑与运动协调和联想学习密切相关，两者都受到压力的调节。压力会引发易感人群的小脑性共济失调，还能增强联想学习。我们最近发现，小鼠在急性嗅觉应激时释放的去甲肾上腺素促进了GluR2基因的转录，并改变了兴奋性突触向小脑抑制性中间神经元的传递。此外，我们发现，这种应激诱导的突触GluR2表达的增加具有重要的后果，因为它显着增强了小脑星状细胞的活性。这些抑制性中间神经元改变浦肯野细胞的放电，从而控制运动 协调和学习。因此，我们认为应激促进了GluR2基因的转录，从而改变了学习诱导的突触可塑性。这为压力调节联想学习和记忆提供了一种新的机制。这项建议的主要目的是了解这种应激诱导的转录依赖开关的机制和功能后果。我们的中心假设是，应激激素去甲肾上腺素通过GluR2基因的表观遗传重塑增加了含有GluR2的突触受体的数量，从而改变了由联想学习诱导的突触可塑性。目的：1.探讨应激诱导星状细胞GluR2基因转录增加的可能机制。我们将研究两个转录调控因子的作用。1)转录激活因子CREB，促进GluR2转录。我们将测试去甲肾上腺素是否通过激活cAMP/PKA/CREB信号通路来促进GluR2的转录。2)转录抑制因子REST与GluR2启动子区域结合，募集组蛋白去乙酰酶，从而抑制GluR2基因的表达。我们验证了应激通过染色质重塑增加GluR2 mRNA的假设。目的2.研究应激诱导的GluR2转录增强对学习依赖型突触可塑性的影响。我们将测试压力增强依赖联想学习的突触可塑性和减弱灭绝诱导的星状细胞逆转的预测。这项拟议的研究旨在确定应激诱导的神经元间功能变化如何改变学习过程中观察到的突触可塑性。它还可能提供关于压力如何触发小脑性共济失调的见解。GluR2基因转录的改变导致了许多神经疾病，包括应激诱导的抑郁和缺血诱导的神经元死亡。拟议中的研究结果与我们对许多与应激相关的神经疾病的理解有关。

DESCRIPTION (provided by applicant): The cerebellum is critically involved in motor coordination and associative learning, both of which are regulated by stress. Stress can trigger cerebellar ataxia in susceptible individuals and also enhances associative learning. We have recently shown that noradrenaline released during an acute olfactory stress in mice promotes GluR2 gene transcription and alters excitatory synaptic transmission onto cerebellar inhibitory interneurons. In addition we found that this stress-induced increase in synaptic GluR2 expression has important consequences because it markedly enhances the activity of cerebellar stellate cells. These inhibitory interneurons alter Purkinje cell firing, and thereby control motor coordination and learning. Therefore we propose that stress enhances GluR2 gene transcription and consequently alters learning-induced synaptic plasticity. This provides a novel mechanism by which stress can regulate associative learning and memory. The primary objective in this proposal is to understand the mechanisms and functional consequences of this stress-induced transcriptional dependent switch. Our central hypothesis is that the stress hormone, noradrenaline, increases the number of synaptic GluR2-containing receptors via epigenetic remodeling of the GluR2 gene, thereby altering the synaptic plasticity that is induced by associative learning. The specific aims are: Aim 1. To determine the underlying mechanisms for the stress-induced increase in GluR2 gene transcription in stellate cells. We will examine the role of two transcriptional regulators. 1) The transcriptional activator CREB which promotes GluR2 transcription. We will test whether noradrenaline promotes GluR2 transcription via activation of cAMP/PKA/CREB signaling pathways. 2) The transcriptional repressor REST binds to the GluR2 promoter region and recruits histone deacetylases which can silence GluR2 gene expression. We test the hypothesis that stress acts via chromatin remodeling to increase GluR2 mRNA. Aim 2. To examine the consequences of a stress-induced enhancement of GluR2 transcription on learning-dependent synaptic plasticity. We will test the prediction that stress enhances associative learning-dependent synaptic plasticity and attenuates the extinction-induced reversal in stellate cells. The proposed study is designed to determine how a stress-induced change in interneuron functioning can alter the synaptic plasticity that is observed during learning. It may also provide insights into how stress can act as a trigger for cerebellar ataxias. Alterations in GluR2 gene transcription contribute to a number of neurological disorders, including stress-induced depression and ischemia-induced neuronal death. Findings from the proposed studies are relevant to our understanding of many stress-related neurological disorders.