Effectors of presynaptic cAMP dependent potentiation at mossy fiber synapses_Diversity Supplement

苔藓纤维突触突触前 cAMP 依赖性增强效应器_Diversity Supplement

• 批准号: 10810245
• 负责人: Anis Contractor
• 金额: $ 7.77万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810245
• 关键词: Affect; Affinity; Axon; Behavior; Brain; Brain region; Characteristics; Chemosensitization; Cognition; Complex; Cyclic AMP; Disease; Frequencies; Hippocampus; Interneurons; Mediating; Membrane; Molecular; Neurodevelopmental Disorder; Pattern; Play; Presynaptic Terminals; Probability; Process; Property; Protein Binding Domain; Pyramidal Cells; Role; Stratum Lucidum; Synapses; Synaptic Vesicles; Synaptic plasticity; cognitive process; complement C2a; dentate gyrus; experimental study; granule cell; mossy fiber; neural circuit; neural patterning; postsynaptic; presynaptic; sensor; synaptotagmin; synaptotagmin VII

Abstract: Short term synaptic plasticity is a dynamic process that provides moment to moment fluctuations in synaptic strength, but connecting these dynamic changes to complex cognitive processes has been difficult. The mossy fiber (MF) to CA3 synapse in the hippocampus provides a unique opportunity to assess a highly dynamic synapse in a microcircuit important for pattern separation tasks. This microcircuit is formed by the MF axons of dentate gyrus (DG) granule cells (GC) forming en passant synapses with excitatory CA3 pyramidal cells (PYRs), and local circuit inhibitory Stratum lucidum interneurons (SLINs). Critically, these two synaptic connections are central to the role of the MF as a high pass filter of information from the DG to CA3. The low release probability connections onto PYRs show significant facilitation when activated at modest frequencies. In contrast, the high release probability synapses at SLINs depress during elevated bouts of activity, reducing feedforward inhibition. These compartmentalized presynaptic properties of the MF allow the synapses to function as conditional detonators, filtering information from the DG to CA3 and allowing GC bursting activity to produce suprathreshold post synaptic summation on the CA3 network. Yet the mechanisms that control this fundamental property of this important hippocampal microcircuit are not fully known. Presynaptic Ca2+ sensors are known to mediate a major component of synaptic facilitation. Specifically, the high affinity Ca2+ sensor Synaptotagmin 7 (Syt7) is critical for facilitation at synapses in multiple brain regions, including the MF to CA3 PYR synapse. Yet there remain many outstanding questions about how this specialized sensor controls release. Crucially, it remains unknown what roles Syt7 plays in facilitation and other steps in the synaptic vesicle (SV) cycle. Here, I will address whether the subcellular localization and activity of Syt7 is compartmentalized in MF synaptic terminals, and how this affects the CA3 microcircuit. I will determine whether Syt7 is primarily associated with MF SVs, like other synaptotagmins that control release, or whether it is localized to non-vesicular membranes, where it plays a specialized role in other aspects of the SV cycle such as pool replenishment. Finally, I will examine the unique properties of Syt7 that are bestowed by the C2A Ca2+ binding domains of the protein. Together these experiments will establish how the molecular identity and functional characteristics of Ca2+ sensors define the network properties of the CA3 microcircuit.

摘要： 短时程突触可塑性是一个动态过程，它提供突触可塑性的瞬间波动。 然而，将这些动态变化与复杂的认知过程联系起来是困难的。长满青苔的 海马体中的CA3突触的神经纤维（MF）提供了一个独特的机会来评估高度动态的 微电路中对模式分离任务很重要的突触。这个微电路是由MF轴突形成的， 齿状回（DG）颗粒细胞（GC）与兴奋性CA3锥体细胞形成传递性突触 （PYR）和局部回路抑制性透明层中间神经元（SLIN）。关键是，这两个突触 连接对于MF作为从DG到CA 3的信息的高通滤波器的作用是中心的。低 当以适度的频率激活时，与PYR的释放概率连接显示出显著的易化。 相比之下，SLIN上的高释放概率突触在升高的活动中抑制， 前馈抑制MF的这些分隔的突触前特性允许突触 作为条件引爆器，过滤从DG到CA 3的信息，并允许GC爆发活动， 在CA3网络上产生阈上突触后总和。然而，控制这一点的机制 这种重要海马体微电路的基本特性还不完全清楚。 已知突触前Ca 2+传感器介导突触易化的主要成分。具体而言是 高亲和力Ca 2+传感器Synaptotagmin 7（Syt 7）对于多个脑区域中突触的易化是关键的， 包括MF到CA3 PYR突触。然而，仍然有许多悬而未决的问题， 专门的传感器控制释放。至关重要的是，仍然不知道Syt7在促进和 突触囊泡（SV）周期中的其他步骤。在这里，我将讨论是否亚细胞定位和 Syt7的活性在MF突触末端中被区室化，以及这如何影响CA3微电路。我会 确定Syt7是否主要与MF SV相关，如控制释放的其他突触结合蛋白，或 是否局限于非囊泡膜，在SV的其他方面发挥专门作用 循环，如池补充。最后，我将研究Syt7的独特属性， 蛋白质的C2A Ca2+结合结构域。这些实验将共同确定 Ca 2+传感器的功能特性定义了CA 3微电路的网络特性。