Transcriptional control of activity-dependent synaptic plasticity

描述(申请人提供)：大脑中的抽象神经元可以迅速改变它们的转录特征，以响应感觉输入和内在信号。这种建立和调节突触的基因表达的经验依赖性变化在电路发育和信息处理中发挥着关键作用。我们推测，HDAC4是第II类组蛋白脱乙酰酶家族的成员，穿梭于细胞核和细胞质之间，控制着突触可塑性和空间记忆所必需的转录程序。这一假说基于下列初步结果：i)神经元HDAC4的核输入以及其与神经元染色质和转录因子的相互作用能力受NMDA受体的负面调控；ii)在细胞核中，HDAC4抑制一组有限的基因，这些基因在已知参与突触功能的基因中高度丰富；iii)HDAC4在核中的积累既影响兴奋性突触的结构和强度；iv)HDAC4基因的移帧突变与人类一种罕见的精神发育迟滞有关；v)因此，携带HDAC4截短型基因的小鼠在神经传递和空间记忆方面表现出缺陷。我们建议使用实验室建立的两个独特的动物模型来阐明HDAC4在大脑中的作用。我们已经开发了一种新的化学遗传系统，它能够在活的和行为正常的小鼠中通过药物诱导控制谷氨酸的释放。我们将利用这个系统来确定突触输入在调节HDAC4在体内的定位和转录活性中的作用。在互补性研究中，我们将检验这一假设，即观察到的HDAC4缺陷突变体的记忆丧失是由于突触可塑性缺陷所致。为了实现这一目标，我们将使用光学成像和电生理学来询问这些小鼠的突触。我们预计，这些研究将为神经元转录控制的分子机制提供重要的见解，并最终可能促进神经疾病的新治疗方法的设计。好了！

DESCRIPTION (provided by applicant): Abstract Neurons in the brain can rapidly alter their transcriptional profiles in response to sensory inputs and intrinsic signals. Such experience-dependent changes in expression of genes that build and regulate synapses play a critical role in circuit development and information processing. We hypothesize that HDAC4, a member of the class II histone deacetylase family that shuttles between the nucleus and cytoplasm, controls a transcriptional program essential for synaptic plasticity and spatial memory. This hypothesis is based on the following preliminary results: i) the nuclear import of neuronal HDAC4 and its ability to interact with neuronal chromatin and transcription factors is negatively regulated by NMDA receptors; ii) in the nucleus, HDAC4 represses a restricted group of genes highly enriched in those known to be involved in synaptic function; iii) accumulation of HDAC4 in the nucleus affects both the architecture and strength of excitatory synapses; iv) a frame-shift mutation in the HDAC4 gene has been linked to a rare form of mental retardation in humans; and v) accordingly, mice carrying a truncated form of HDAC4 which mimics the mutant human allele exhibit deficits in neurotransmission and spatial memory. We propose to elucidate the role of HDAC4 in the brain using two unique animal models established in the laboratory. We have developed a new chemical-genetic system that enables drug-inducible control of glutamate release in live and behaving mice. We will take advantage of this system to define the role of synaptic inputs in regulating the localization and transcriptional activity of HDAC4 in vivo. In complementary studies, we will test the hypothesis that memory loss observed of HDAC4-deficient mutants is due to deficits in synaptic plasticity. To attain this goal, we will interrogae synapses of these mice using optical imaging and electrophysiology. We anticipate that these studies will provide important insight to molecular mechanisms of transcriptional control in neurons, and may eventually facilitate the design of new treatments of neurological diseases. !