Transcriptional control of activity-dependent synaptic plasticity

大脑中的神经元可以根据感觉输入和内在信号迅速改变其转录谱。这种建立和调节突触的基因表达的经验依赖性变化在回路发育和信息处理中起着至关重要的作用。我们假设HDAC4是II类组蛋白去乙酰化酶家族的一员，它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。这一假设基于以下初步结果：1)神经元HDAC4的核输入及其与神经元染色质和转录因子相互作用的能力受到NMDA受体的负调控；ii)在细胞核中，HDAC4抑制了一组已知参与突触功能的高度富集的限制性基因；iii)细胞核中HDAC4的积累影响兴奋性突触的结构和强度；iv) HDAC4基因的帧移突变与人类中一种罕见的智力迟钝有关；v)因此，携带HDAC4的截断形式的小鼠，模仿突变的人类等位基因，表现出神经传递和空间记忆的缺陷。我们建议利用实验室建立的两种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，可以通过药物诱导控制活的和行为正常的小鼠的谷氨酸释放。我们将利用这个系统来确定突触输入在体内调节HDAC4的定位和转录活性中的作用。在补充研究中，我们将验证hdac4缺陷突变体的记忆丧失是由于突触可塑性缺陷造成的这一假设。为了实现这一目标，我们将利用光学成像和电生理学来研究这些小鼠的突触。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，并可能最终促进神经系统疾病新疗法的设计。！

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. !