Presynaptic Ca2+ Dynamics, Ca2+ Buffers and the Mechanisms of Facilitation

利用计算模型，研究者研究了突触终末细胞内钙离子内流、扩散和缓冲的时空动力学。研究人员探索的特殊现象是突触反应的短期易化，即仅由几个动作电位引起的突触强度的瞬时增加，并在数十至数百毫秒的时间尺度上衰减。便利化广泛存在于各种系统中，并在神经动力学和信息处理中发挥着重要作用。虽然易化作用依赖于突触前残留钙的积累，但其确切的机制仍存在争议。研究者重点研究了内源性钙缓冲在先前提出的几种不同机制中的作用，以解释促进作用。在这些机制中，包括缓冲饱和，最近的实验表明，它是某些中央突触易化的基础，以及依赖于自由和结合残余钙的易化模型。这项研究集中在两个被广泛用于研究突触传递机制的模型系统上：小龙虾神经肌肉连接和握持突触的听觉盏。在这些突触上获得的丰富的实验数据使得对钙-分泌耦合的详细建模成为可能。这项研究的主要目的之一是探索内源性缓冲特性的变化如何影响动作电位序列中的时空钙浓度分布。这反过来又有助于阐明促进作用的机制，并有助于确定这些突触和其他突触中钙缓冲的作用。这项工作的另一个目的是估计小龙虾NMJ和Hold花冠的内源缓冲区的性质。在这方面，建模方法是必不可少的：除了总体缓冲能力外，大多数突触的特定缓冲特性是无法直接测量的。研究人员将计算机工具应用于研究一个基本的生物过程，即细胞内钙离子的运动。众所周知，钙调节大量重要的生物事件，如基因转录、肌肉收缩、免疫系统反应等。为了了解单个元素如何调节这种AdiVerse生物反应，有必要详细了解细胞内钙浓度是如何控制的。这对于更好地理解突触传递尤其重要，突触传递是研究人员工作的中心。在突触传递中，钙进入突触会导致一种神经递质化学物质的释放，这种化学物质与邻近神经元的受体结合，使电活动从一个细胞传递到下一个细胞。这是神经系统中神经元之间交流的基本过程。有趣的是，两个神经元之间突触连接的强度并不是一成不变的，而是在不断变化。这位研究人员探索了钙的积累如何导致突触暂时增加(促进)它们的力量。与其他形式的突触变化(称为突触可塑性)一样，这种促进作用必须在神经系统的功能中发挥重要作用。除了进一步阐明突触传递机制的直接目标外，对细胞内钙动力学的研究还有助于揭示其他也受钙控制的重要生物过程。最后，这项工作有助于扩大计算方法在生物科学中的使用，这对于保持目前生物学的快速发展是必要的。

Using computational modeling, the investigator studies thespatiotemporal dynamics of intracellular calcium influx, diffusionand buffering in a synaptic terminal. The particular phenomenonexplored by the investigator is the short-term facilitation ofsynaptic response, that is, the transient increase in synapticstrength elicited with just a few action potentials, and decayingon time scales of tens to hundreds of milliseconds. Facilitationis observed in a wide variety of systems, and must play animportant role in neural dynamics and information processing. Although facilitation is known to depend on the presynapticaccumulation of residual calcium, its precise mechanisms are stillunder debate. The investigator focuses on the role of endogenouscalcium buffers in several different mechanisms previouslyproposed to explain facilitation. Among such mechanisms is buffersaturation, recently shown experimentally to underlie facilitationat certain central synapses, and a facilitation model relying onboth free and bound residual calcium. The study concentrates ontwo model systems that have been widely used to explore themechanisms of synaptic transmission: the crayfish neuromuscularjunction and the auditory calyx of Held synapse. The abundance ofexperimental data obtained at these synapses allows detailedmodeling of the calcium-secretion coupling. One of the main goalsof this study is to explore how variations in endogenous bufferingcharacteristics affect the spatiotemporal calcium concentrationprofile during trains of action potentials. This in turn helps inelucidating the mechanisms of facilitation and in ascertaining therole of calcium buffers in these and other synapses. Anotherobjective of this work is to estimate the properties of endogenousbuffers at the crayfish NMJ and at the calyx of Held. A modelingapproach is indispensable in this respect: apart from the over-allbuffering capacity, the specific buffering properties areinaccessible to direct measurement at most synapses. The investigator applies computational tools to the study ofa fundamental biological process, that of the movement of calciumions inside a cell. It is known that calcium regulates a vastnumber of crucial biological events, such as gene transcription,muscle contraction, immune system response, and many others. Inorder to understand how a single element can regulate such adiverse set of biological reactions, it is necessary to know indetail how calcium concentration is controlled inside a cell. This is particularly important for a better understanding ofsynaptic transmission, which is at the center of theinvestigator's work. In synaptic transmission, the entry ofcalcium into the synapse causes the release of a neurotransmitterchemical, binding of which to the receptors of the neighboringneuron allows the electric activity to be transmitted from onecell to the next. This is the fundamental process ofcommunication between neurons in the nervous system. It isinteresting that the strength of the synaptic connection betweentwo neurons does not remain the same, but is constantly changing. The investigator explores how the accumulation of calcium causessome synapses to temporarily increase (facilitate) their strength. Along with other forms of synaptic change (termed synapticplasticity), such facilitation must play an important role in thefunctioning of the nervous system. Apart from the immediate goalof further elucidating the synaptic transmission mechanisms, thisstudy of intracellular calcium dynamics helps to shed light onother important biological processes that are also controlled bycalcium. Finally, this work contributes to the widening of theuse of computational methods in biosciences, which is necessary inorder to maintain the current rapid progress in biology.