Assembling the Presynaptic Junction

组装突触前连接

• 批准号: 7227756
• 负责人: Craig C Garner
• 金额: $ 35.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227756
• 关键词: Address; Antibodies; Appendix; Biochemical; Biogenesis; Cell-Cell Adhesion; Chromogranin A; Chromosome Pairing; Class; Cleaved cell; Complementary DNA; Complex; Cues; Cytoskeletal Proteins; Data; Degenerative Disorder; Dense Core Vesicle; Development; Docking; Electrons; Excitatory Synapse; Exocytosis; Glutamate Receptor; Glutamates; Golgi Apparatus; Hippocampus (Brain); Hour; Image; Individual; Inhibitory Synapse; Lead; Localized; Maintenance; Mass Spectrum Analysis; Modeling; Molecular; Nature; Nerve; Neurobiology; Neurons; Numbers; Play; Proteins; Proteomics; Publishing; Purpose; Rain; Recruitment Activity; Role; Role playing therapy; Series; Signal Transduction; Site; Staging; Structural Protein; Structure; Synapses; Synaptic Cleft; Synaptic Vesicles; Testing; Time; Transport Vesicles; Vesicle; Work; cytomatrix; design; developmental disease; interest; neural circuit; neurotransmitter release; postsynaptic; presynaptic; protein protein interaction; protein transport; release factor; research study; synaptic function; synaptogenesis; time use; trans-Golgi Network

DESCRIPTION (provided by applicant): Synapses of the mammalian CNS are highly specialized cellular junctions designed for rapid and regulated signaling between nerve cells and their targets. Morphologically, synapses are asymmetric structures composed of a presynaptic bouton filled with synaptic vesicles (SVs), a synaptic cleft and a postsynaptic specialization. Proper synaptic function requires the precise functional integration of numerous, appropriate localized components. However, little is known about the molecular and cellular mechanisms underlying the assembly of CNS synapses. Recent advances in determining the molecular composition of CNS synapses has allowed neuroscientists to address a number of fundamental questions regarding the assembly and function of CNS synapses. In our recent studies, we have begun to analyze how presynaptic active zones (AZs) are formed. These studies have lead to the discovery of two AZ cytoskeletal proteins, Piccolo and Bassoon, which appear to be central organizers of these sites of synaptic vesicle exocytosis and neurotransmitter release. More recently we have examined when, how and in what form these AZ proteins are transported and recruited into nascent synapses. These studies have answered several basic neurobiological questions regarding the timing of synaptogenesis and whether AZ formation precedes the formation of the postsynapse. In particular, we have found that glutamatergic synapses form in less than two hours and that AZs form prior to the postsynapse. Mechanistically, we could show that the rapid formation of AZs (less than 20 mins) appears to be accomplished by the fusion of a small number of AZ precursor vesicles carrying numerous components of the AZ that are essential for SV exocytosis. Experiments outlined in this proposal will test the hypothesis that these putative AZ precursor vesicles are not only essential for the assembly of functional AZs, but also for the formation of a functional postysynapse. This will be accomplished by determining the molecular composition of these precursor vesicles, whether their fusion at nascent synaptic sites is required for AZ formation and whether they facilitate the release of factors that promote the clustering of postsynaptic glutamate receptors and structural proteins. These studies are critical to the understanding of how synapses are formed during normal development, as well as in developmental disorders and degenerative diseases.

描述（由申请人提供）：哺乳动物中枢神经系统的突触是高度专业化的细胞连接，设计用于神经细胞与其靶标之间快速且受调节的信号传导。从形态学上来说，突触是一种不对称结构，由充满突触小泡（SV）的突触前波团、突触间隙和突触后特化组成。正确的突触功能需要大量适当的局部组件的精确功能整合。然而，人们对中枢神经系统突触组装的分子和细胞机制知之甚少。确定中枢神经系统突触分子组成的最新进展使神经科学家能够解决有关中枢神经系统突触组装和功能的许多基本问题。在我们最近的研究中，我们开始分析突触前活跃区（AZ）是如何形成的。这些研究发现了两种 AZ 细胞骨架蛋白 Piccolo 和 Bassoon，它们似乎是突触小泡胞吐作用和神经递质释放这些位点的中心组织者。最近，我们研究了这些 AZ 蛋白何时、如何以及以何种形式被运输和招募到新生突触中。这些研究回答了一些关于突触发生时间以及 AZ 形成是否先于突触后形成的基本神经生物学问题。特别是，我们发现谷氨酸能突触在不到两小时内形成，并且 AZ 在突触后形成之前形成。从机制上讲，我们可以证明 AZ 的快速形成（不到 20 分钟）似乎是通过少量 AZ 前体囊泡的融合来完成的，这些前体囊泡携带大量 AZ 成分，这些成分对于 SV 胞吐作用至关重要。该提案中概述的实验将检验以下假设：这些假定的 AZ 前体囊泡不仅对于功能性 AZ 的组装至关重要，而且对于功能性后突触的形成也至关重要。这将通过确定这些前体囊泡的分子组成、AZ形成是否需要它们在新生突触位点的融合以及它们是否促进促进突触后谷氨酸受体和结构蛋白聚集的因子的释放来实现。这些研究对于理解正常发育过程中以及发育障碍和退行性疾病中突触如何形成至关重要。

项目成果

Dynein light chain regulates axonal trafficking and synaptic levels of Bassoon.

动力蛋白轻链调节巴松管的轴突运输和突触水平。

• 发表时间: 2009-04-20
• 作者: Fejtova, Anna;Davydova, Daria;Bischof, Ferdinand;Lazarevic, Vesna;Altrock, Wilko D;Romorini, Stefano;Schone, Cornelia;Zuschratter, Werner;Kreutz, Michael R;Garner, Craig C;Ziv, Noam E;Gundelfinger, Eckart D
• 通讯作者: Gundelfinger, Eckart D

Piccolo regulates the dynamic assembly of presynaptic F-actin.

Piccolo 调节突触前 F-肌动蛋白的动态组装。

• 发表时间: 2011-10-05
• 作者: Waites, Clarissa L;Leal;Andlauer, Till F M;Sigrist, Stefan J;Garner, Craig C
• 通讯作者: Garner, Craig C

Episodic-like memory in Ts65Dn, a mouse model of Down syndrome.

Ts65Dn（唐氏综合症小鼠模型）的情景式记忆。

• 发表时间: 2008-03-17
• 影响因子: 2.7
• 作者: Fernandez, Fabian;Garner, Craig C
• 通讯作者: Garner, Craig C

Piccolo modulation of Synapsin1a dynamics regulates synaptic vesicle exocytosis.

Synapsin1a 动力学的 Piccolo 调节可调节突触小泡胞吐作用。

• 发表时间: 2008-06-02
• 作者: Leal;Waites, Clarissa L;Terry;Zamorano, Pedro;Gundelfinger, Eckart D;Garner, Craig C
• 通讯作者: Garner, Craig C

Local sharing as a predominant determinant of synaptic matrix molecular dynamics.

局部共享是突触基质分子动力学的主要决定因素。

• 发表时间: 2006-09
• 影响因子: 9.8
• 作者: Tsuriel, Shlomo;Geva, Ran;Zamorano, Pedro;Dresbach, Thomas;Boeckers, Tobias;Gundelfinger, Eckart D;Garner, Craig C;Ziv, Noam E
• 通讯作者: Ziv, Noam E