Use dependent regulation of the coupling distance between Ca2+ channels and release sensor as a mechanism of long-term plasticity

中枢神经系统的信息处理依赖于快速的化学突触传递及其通过突触可塑性调节。在动作电位介导的突触前末端电压门控Ca2+通道打开后，流入的Ca2+通过结合囊泡释放传感器蛋白在突触活性区触发充满递质的突触囊泡（SVs）的融合。Ca2+在一个开放的通道口周围建立一个陡峭的、短暂的浓度梯度，随着距离通道的增加而迅速减少。这使得通道与释放传感器之间的空间耦合距离成为突触传递效能的关键参数。迄今为止，已经区分了两种主要的耦合结构：紧密的纳米畴耦合和松散的微畴耦合。紧耦合有利于高突触效能，特别是高SVs释放概率，而松耦合被认为提供了更多的调节选择。耦合距离本身是如何调节的，目前还不是很清楚。在被研究的突触中，一个从松散的微结构域到紧密的纳米结构域耦合的发育开关被描述为显著改变了突触的功效。突触效能进一步受到突触前长期可塑性的调节，同样以年龄依赖的方式。幼突触倾向于长期增强（LTP），而成熟突触则根据经典的可塑性规律诱导LTP和长期抑制（LTD）。活动区地形与长期塑性之间的关系目前还不清楚。在这一提议中，提出了以下假设：年轻突触偏向LTP，因为它们具有松散的微域耦合，并且优先诱导耦合距离的收紧，与可塑性协议的细节无关。成熟突触以紧密的纳米结构域耦合运作，LTD增加了耦合距离。LTP可能进一步加强成熟突触的耦合，但很可能涉及其他机制，特别是额外释放位点的募集。该项目将活动区地形的年龄差异与长期可塑性的年龄差异联系起来，从而建立活动区的过程和重排与长期可塑性是如何相互影响的。由于释放和可塑性是神经元信息处理和皮层图谱构建的核心，该项目解决了我们对大脑突触成熟和编码的理解的主要空白。

Information processing in the central nervous system relies on rapid chemical synaptic transmission and its modulation via synaptic plasticity. Upon action potential - mediated depolarization of a presynaptic terminal voltage-gated Ca2+ channels open and the inflowing Ca2+ triggers the fusion of transmitter-filled synaptic vesicles (SVs) at the synaptic active zone by binding to vesicular release sensor proteins. Ca2+ builds a steep, short-lived concentration gradient around the mouth of an open channel that rapidly diminishes with increasing distance from the channel. This makes the spatial coupling distances between channels and release sensors a key parameter of the efficacy of synaptic transmission. Two principle coupling configurations have been distinguished to date: tight nanodomain coupling and loose microdomain coupling. Tight coupling favors high synaptic efficacy, in particular high probability of release of SVs, while loose coupling is thought to provide more options for regulation. How the coupling distance itself is regulated is not well understood at present. At investigated synapses a developmental switch from loose microdomain to tight nanodomain coupling has been described that significantly altered synaptic efficacy. Synaptic efficacy is further regulated by presynaptic long-term plasticity, again in an age-dependent manner. Synapses in young cortex are biased towards long-term potentiation (LTP), while at mature synapses both, LTP and long-term depression (LTD) are induced according to classical plasticity rules. The relationships between active zone topographies and long-term plasticity are largely unclear at present. In this proposal, the following hypotheses are addressed: Young synapses are biased towards LTP because they have loose microdomain coupling and a tightening of the coupling distance is induced preferentially, independent of the details of the plasticity protocol. Mature synapses operate with tight nanodomain coupling and LTD increases the coupling distance. LTP may further tighten coupling at mature synapses but most likely involves further mechanisms, in particular recruitment of additional release sites. The project relates age-dependent differences in active zone topography to age-dependent differences in long-term plasticity, hence, establishing how processes and rearrangements at the active zone and long-term plasticity mutually influence each other. Since release and plasticity are at the core of neuronal information processing and cortical map construction, the project addresses a major gap in our understanding of synapse maturation and coding in the brain.