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

描述（由申请人提供）：小脑主要参与运动协调和联想学习，两者都受压力调节。压力可以触发易感个体的小脑共济失调，也可以增强联想学习。我们最近发现，在小鼠急性嗅觉应激过程中释放的去甲肾上腺素促进GluR 2基因转录，并改变兴奋性突触传递到小脑抑制性中间神经元。此外，我们发现，这种应激诱导的突触GluR 2表达的增加具有重要的后果，因为它显着增强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放电，从而控制运动神经元的运动。 协调和学习。因此，我们认为，压力增强GluR 2基因的转录，从而改变学习诱导的突触可塑性。这提供了一种新的机制，压力可以调节联想学习和记忆。在这个建议的主要目标是了解这种压力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，增加突触GluR 2受体的数量通过表观遗传重塑的GluR 2基因，从而改变突触可塑性，诱导的联想学习。具体目标是：目标1。探讨应激诱导星状细胞GluR 2基因转录增加的机制。我们将研究两个转录调节因子的作用。1)促进GluR 2转录的转录激活因子CREB。我们将测试去甲肾上腺素是否通过激活cAMP/PKA/CREB信号通路促进GluR 2转录。2)转录抑制因子REST与GluR 2启动子区域结合，并募集组蛋白脱乙酰酶，其可以沉默GluR 2基因表达。我们测试的假设，压力通过染色质重塑，以增加GluR 2 mRNA的作用。目标2.研究应激诱导的GluR 2转录增强对学习依赖性突触可塑性的影响。我们将测试的预测，压力增强联想学习依赖的突触可塑性和衰减的抑制诱导逆转星状细胞。这项研究的目的是确定在学习过程中观察到的应激诱导的中间神经元功能变化如何改变突触可塑性。它也可能提供关于压力如何触发小脑共济失调的见解。GluR 2基因转录的改变导致许多神经系统疾病，包括应激诱导的抑郁症和缺血诱导的神经元死亡。这些研究的结果与我们对许多与压力相关的神经系统疾病的理解有关。

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.