Effectors of presynaptic cAMP dependent potentiation at mossy fiber synapses_Diversity Supplement

摘要： 突触的短期可塑性是一个动态过程，它在突触中提供瞬间到瞬间的波动 但将这些动态变化与复杂的认知过程联系起来一直是困难的。长满苔藓的 海马区纤维(MF)到CA3突触提供了一个独特的机会来评估高度动态的 微电路中的突触对模式分离任务很重要。这个微电路是由 齿状回颗粒细胞(GC)与兴奋性CA3锥体细胞形成传递性突触 (PYRs)和局部环路抑制层中间神经元(SLIN)。关键的是，这两个突触 连接对于作为从DG到CA3的信息的高通过滤器的MF的角色至关重要。低谷 当以中等频率激活时，释放概率连接到PYR上显示出显著的促进作用。 相比之下，SLIN的高释放概率突触在活动增加期间受到抑制，从而减少 前馈抑制。这些隔断化的突触前特性允许突触 充当条件引爆器，将信息从DG过滤到CA3，并允许GC爆裂活动 在CA3网络上产生阈值上的突触后总和。然而，控制这一点的机制 这一重要的海马区微电路的基本性质尚不完全清楚。 突触前Ca~(2+)感受器是突触易化的重要组成部分。具体地说， 高亲和力的钙离子感受器突触素7(Syt7)在多个脑区的突触易化中起关键作用， 包括Mf到CA3PYR突触。然而，关于这一点如何做到这一点，仍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，目前尚不清楚Syt7在促进和 突触小泡(SV)周期的其他步骤。在这里，我将讨论亚细胞定位和 Syt7的活动在MF突触终末被区分开来，以及这是如何影响CA3微电路的。这就做 确定Syt7是否主要与MF SVS相关，就像其他控制释放的突触素一样，或者 它是否局限于非囊泡膜，在SV的其他方面发挥特殊作用 循环，如池补给。最后，我将研究Syt7的独特属性，这些属性由 该蛋白的C2a钙结合结构域。这些实验将一起确定分子身份如何 而钙传感器的功能特性决定了CA3微电路的网络特性。

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.