Mechanisms of Dendritic Spine Elimination

树突棘消除机制

基本信息

批准号：
9930698
负责人：
Karen Zito
金额：
$ 4.33万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2009-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9930698
关键词：
Address Adult Bipolar Disorder Brain Calcium Cerebral cortex Chemosensitization Color Coupled Data Dendritic Spines Development Disease Electron Microscopy Electrophysiology (science)Epilepsy Etiology Excitatory Synapse Fragile X Syndrome Glutamate Receptor Glutamates Goals Growth Human Image Imaging Techniques Imaging technology Immunoelectron Microscopy Individual Ions Knowledge Lead Learning Measures Memory Mental Retardation Molecular Monitor Morphology Neurodevelopmental Disorder Pattern Pharmacology Play Proteins Research Proposals Role Schizophrenia Signal Pathway Signal Transduction Synapses Time Vertebral column X-Linked Mental Retardation autism spectrum disorder brain circuitry density experience experimental study fluorescence lifetime imaging hippocampal pyramidal neuron in vivo innovation nervous system disorder neural circuit neuromechanism photolysis postnatal development postsynaptic reconstitution synaptic function synaptogenesis therapeutic development two-photon

项目摘要

Abstract The growth and retraction of dendritic spines with synapse formation and elimination is thought to underlie experience-dependent changes in brain circuitry during development and in the adult brain, and also may play a role in neurodevelopmental disorders. While much focus has been given to spine growth and associated synapse formation as a key step in the development of brain circuits, the mechanisms of spine retraction and synapse disassembly are ill-defined. During late postnatal development, after initial connectivity has been established, dendritic spine densities decrease and half of all synapses are lost in some regions of the cortex. This period coincides with a period of intense learning, suggesting that spine and synapse elimination may have an integral role in learning and memory. Indeed, many neurological disorders that result in mental retardation have been associated with spine loss and spine morphology changes. The primary goal of the proposed studies is to determine the mechanisms that govern the retraction of dendritic spines and the disassembly of synapses during brain development, plasticity, and disease. We have recently shown that spine shrinkage is initiated by both input-specific and locally competitive activity patterns that lead to synaptic weakening and that spine retraction is tightly coupled to disassembly of the postsynaptic density. We currently have three aims. First, we will determine the molecular mechanisms that drive input-specific spine shrinkage and retraction and synaptic weakening. Second, we will define the cellular and molecular signaling mechanisms by which competition between neighboring synapses drives spine shrinkage and retraction, and what role these competitive mechanisms play during circuit plasticity in vivo. Finally, we will determine how synaptic interactions and molecular composition are regulated during input-specific and heterosynaptic spine shrinkage and retraction. To achieve these goals, we will use focal photolysis of caged glutamate to stimulate individual spines, combined with electrophysiology to measure spine synapse function, calcium and fluorescence lifetime imaging to measure real-time signaling in dendritic microdomains, and electron microscopy to monitor pre- and postsynaptic ultrastructural changes and molecular alterations during spine retraction. The combined use of advanced two-photon imaging techniques, electrophysiology, and electron microscopy at single synapses will provide an innovative and powerful way to identify the mechanisms that govern the retraction and disassembly of spine synapses. Results from our experiments will rigorously address the mechanisms of spine retraction and synapse disassembly, thereby filling major gaps in our current understanding of neural circuit refinement during development and experience-dependent plasticity. Ultimately, basic knowledge of the mechanisms of spine elimination has strong potential to facilitate the development of therapeutics for neurological diseases.

抽象的人们认为，树突状刺的生长和缩回是突触形成和消除的在开发过程中和成年人期间脑电路的经验依赖性变化是基础大脑，也可能在神经发育障碍中发挥作用。虽然重点是将脊柱生长和相关的突触形成作为开发的关键步骤脑电路，脊柱缩回的机制和突触拆卸的机制是不明的。在产后晚期发育期间，建立初始连通性后，树突状脊柱在皮质的某些地区，所有突触的密度降低，一半的突触损失。这个时期与一段时间的学习时期相吻合，表明脊柱和突触消除可能在学习和记忆中起着不可或缺的作用。确实，许多导致的神经系统疾病智力低下与脊柱丧失和脊柱形态变化有关。这拟议研究的主要目标是确定控制缩回的机制在大脑发育，可塑性和疾病。我们最近表明，脊柱收缩均由输入特异性和局部竞争性活动模式导致突触弱，脊柱缩回是紧密耦合到突触后密度的拆卸。我们目前有三个目标。第一的，我们将确定驱动输入特异性脊柱收缩和的分子机制缩回和突触减弱。其次，我们将定义细胞和分子信号传导相邻突触之间竞争的机制驱动脊柱收缩和缩回以及这些竞争机制在体内电路可塑性期间起什么作用。最后，我们将确定如何调节突触相互作用和分子组成在输入特异性和异质性脊柱收缩和缩回期间。为了实现这些目标，我们将使用笼谷氨酸的局灶性光解来刺激单个棘突，并结合测量脊柱突触功能，钙和荧光寿命成像的电生理学测量树枝状微区和电子显微镜中的实时信号传导以监测脊柱回缩期间的突触前和突触后超微结构变化和分子改变。高级两光子成像技术，电生理学和电子的联合使用单个突触时的显微镜将提供一种创新且有力的方式来识别控制脊柱突触的缩回和拆卸的机制。我们的结果实验将严格解决脊柱缩回和突触的机制拆卸，从而填补了我们当前对神经回路完善的理解中的主要空白在开发和经验依赖性可塑性期间。最终，对消除脊柱的机制具有促进发展的强大潜力神经疾病的治疗剂。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heterosynaptic structural plasticity on local dendritic segments of hippocampal CA1 neurons.

DOI：
10.1016/j.celrep.2014.12.016
发表时间：
2015-01-13
期刊：
Cell reports
影响因子：
8.8
作者：
Oh WC;Parajuli LK;Zito K
通讯作者：
Zito K

Loss of PSD-95 enrichment is not a prerequisite for spine retraction.

DOI：
10.1523/jneurosci.6662-10.2011
发表时间：
2011-08-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Woods GF;Oh WC;Boudewyn LC;Mikula SK;Zito K
通讯作者：
Zito K

Ion flux-independent NMDA receptor signaling.

DOI：
10.1016/j.neuropharm.2022.109019
发表时间：
2022-06-01
期刊：
NEUROPHARMACOLOGY
影响因子：
4.7
作者：
Park, Deborah K.;Stein, Ivar S.;Zito, Karen
通讯作者：
Zito, Karen

Dendritic Spine Elimination: Molecular Mechanisms and Implications.

DOI：
10.1177/1073858418769644
发表时间：
2019-03
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
0
作者：
Stein IS;Zito K
通讯作者：
Zito K

Breaking it down: the ubiquitin proteasome system in neuronal morphogenesis.