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Signaling Mechanisms Regulating Rho GTPase-Dependent Synaptic Plasticity Underlying Memory in Health and Disease

调节健康和疾病记忆中 Rho GTP 酶依赖性突触可塑性的信号机制

基本信息

批准号：
10587076
负责人：
Kimberly R Tolias
金额：
$ 191.24万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587076
关键词：
Actins Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Automobile Driving Behavioral Binding Biochemistry Brain Brain Diseases Characteristics Cognition Disorders Cognitive Couples Coupling Development Disease Electrophysiology (science)Ephrin B Receptor Equilibrium Excitatory Synapse Functional disorder GTPase-Activating Proteins Guanine Nucleotide Exchange Factors Guanine Nucleotides Guanosine Triphosphate Phosphohydrolases Health Hippocampus (Brain)Human Impairment Injections Intellectual functioning disability Knockout Mice Learning Mediating Memory Memory impairment Mental Depression Modeling Mus Neurons Pathway interactions Pharmacology Play Post-Traumatic Stress Disorders Process Regulation Resolution Role Schizophrenia Signal Transduction Signal Transduction Pathway Specificity Synapses Synaptic Receptors Synaptic plasticity System Testing Vertebral column Viral autism spectrum disorder brain remodeling cognitive function conditional knockout confocal imaging dentate gyrus flexibility forgetting functional plasticity inhibitor insight memory process memory retention mouse genetics mouse model novel therapeutic intervention protein complex rac1 GTP-Binding Protein receptor rho GTP-Binding Proteins rhoA GTP-Binding Protein spatiotemporal synaptogenesis trait viral gene delivery

项目摘要

PROJECT SUMMARY The ability to remember and the capacity to forget are both required for a functional memory system, whereas their dysfunction is a common feature of cognitive disorders such as Alzheimer’s Disease (AD). It is unclear, however, how these opposing memory processes are balanced. Memory formation is driven by activity- dependent synaptic changes in neurons involved in the memory trace. Rho GTPases regulate this synaptic plasticity by controlling actin dynamics. Although Rac1 and RhoA can promote learning and memory, Rac1 also plays a key role in forgetting. To function properly, Rho GTPases require precise spatiotemporal regulation that is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which not only control Rho GTPase activity, but also provide signaling specificity via interactions with upstream receptors and downstream effectors. We previously identified the Rac1-GEF Tiam1 as a critical regulator of spine/synapse development that couples synaptic receptors like NMDAR and EphB2 to localized Rac1-dependent actin remodeling. Tiam1 forms a GEF/GAP complex with the Rac1-GAP/RhoA-GEF Bcr, which bidirectionally regulates excitatory synapse development by dynamically controlling synaptic Rac1 activity. Following Bcr loss, excessive EphB-induced Tiam1-Rac1 signaling drives EphB internalization and spine retraction rather than synaptogenesis. However, the role of this GEF/GAP complex in the adult brain remains unclear. Using Tiam1 conditional knockout mice, we recently found that Tiam1 restricts NMDAR function and synaptic plasticity in the dentate gyrus of adult mice and limits learning and memory, in contrast to Bcr. Thus, we hypothesize that Tiam1 and Bcr cooperate in the adult brain to provide spatiotemporal control and signaling specificity to Rho GTPases, enabling dynamic regulation of synaptic plasticity critical for learning, memory, and forgetting. Moreover, Ab- induced Tiam1-Rac1 dysregulation likely drives aberrant synaptic plasticity that contributes to AD-associated memory impairments, and targeting this pathway will alleviate these deficits. To test this hypothesis, we aim to: (1) uncover the mechanisms by which Tiam1/Bcr dynamically regulate Rho GTPase signaling and synaptic plasticity important for learning and memory; (2) determine how Tiam1/Bcr regulates hippocampal-dependent learning, memory, and forgetting in adult mice; and (3) elucidate the role of Tiam1-Rac1 in Ab-induced EphB/NMDAR internalization and synapse loss, and determine how targeting this pathway affects synaptic plasticity and learning and memory deficits in an AD mouse model. We will accomplish this using a combination of mouse genetics, viral injections, confocal imaging, biochemistry, pharmacology, electrophysiology, and behavioral analyses. Our study should provide critical insight into Rho GTPase-dependent mechanisms that control normal synaptic plasticity underlying learning, memory, and forgetting as well as Ab-induced synaptic dysfunction. Furthermore, it will establish whether targeting Tiam1-Rac1 signaling rescues synaptic plasticity and memory deficits in an AD mouse model, which may aid in the development of a new therapeutic strategy for AD.

项目摘要记忆能力和遗忘能力都是功能性记忆系统所必需的，而它们的功能障碍是认知障碍如阿尔茨海默病（AD）的共同特征。目前还不清楚，然而，这些对立的记忆过程是如何平衡的。记忆的形成是由活动驱动的参与记忆痕迹的神经元的依赖性突触变化。Rho GTP酶调节这种突触通过控制肌动蛋白动力学来实现可塑性。虽然Rac 1和RhoA可以促进学习和记忆，但Rac 1也在遗忘中起着关键作用。为了正常工作，Rho GTP酶需要精确的时空调节，由鸟嘌呤核苷酸交换因子（GEF）和GTP酶激活蛋白（GAP）介导，不仅控制Rho GT3活性，而且通过与上游受体的相互作用提供信号传导特异性和下游效应器。我们以前确定Rac 1-GEF Tiam 1作为脊柱/突触的关键调节因子将突触受体（如NMDAR和EphB 2）与局部Rac 1依赖性肌动蛋白偶联的发育重塑Tiam 1与Rac 1-GAP/RhoA-GEF Bcr形成GEF/GAP复合物，其双向通过动态控制突触Rac 1活性调节兴奋性突触发育。在Bcr丢失后，过量的EphB诱导的Tiam 1-Rac 1信号传导驱动EphB内化和棘回缩，而不是突触发生然而，这种GEF/GAP复合物在成人大脑中的作用仍不清楚。使用Tiam 1 在条件性基因敲除小鼠中，我们最近发现Tiam 1限制了NMDAR的功能和突触可塑性，成年小鼠的齿状回和限制学习和记忆，与Bcr相反。因此，我们假设Tiam 1 和Bcr在成人脑中合作以提供对Rho GTP酶的时空控制和信号传导特异性，能够动态调节对学习、记忆和遗忘至关重要的突触可塑性。此外，AB- 诱导的Tiam 1-Rac 1失调可能驱动异常的突触可塑性，导致AD相关的记忆障碍，靶向这一途径将缓解这些缺陷。为了验证这一假设，我们的目标是： (1)揭示Tiam 1/Bcr动态调节Rho GT3信号和突触的机制。可塑性对学习和记忆的重要性;（2）确定Tiam 1/Bcr如何调节依赖于大脑的可塑性，（3）阐明Tiam 1-Rac 1在Ab诱导的小鼠学习、记忆和遗忘中的作用。 EphB/NMDAR内化和突触丢失，并确定如何靶向这一途径影响突触在AD小鼠模型中的可塑性和学习记忆缺陷。我们将使用一个组合来实现这一点，小鼠遗传学，病毒注射，共聚焦成像，生物化学，药理学，电生理学，行为分析我们的研究应该为Rho GTP酶依赖性机制提供重要的见解，控制正常的突触可塑性，这些可塑性是学习、记忆和遗忘以及Ab诱导的突触可塑性的基础。功能障碍此外，它将确定靶向Tiam 1-Rac 1信号传导是否能挽救突触可塑性，在AD小鼠模型中的记忆缺陷，这可能有助于开发AD的新治疗策略。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Emerging Roles of BAI Adhesion-GPCRs in Synapse Development and Plasticity.

DOI：
10.1155/2016/8301737
发表时间：
2016
期刊：
Neural plasticity
影响因子：
3.1
作者：
Duman JG;Tu YK;Tolias KF
通讯作者：
Tolias KF

The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites.

DOI：
10.1523/jneurosci.3978-12.2013
发表时间：
2013-04-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Duman JG;Tzeng CP;Tu YK;Munjal T;Schwechter B;Ho TS;Tolias KF
通讯作者：
Tolias KF

The small GTPase RhoA is required for proper locomotor circuit assembly.