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

使用 Ca2 通道和释放传感器之间的耦合距离的依赖性调节作为长期可塑性的机制

• 批准号: 459058603
• 负责人: Professor Dr. Hartmut Schmidt
• 金额: --
• 依托单位: Carl-Ludwig-Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/459058603?language=en
• 关键词: Use; dependent; regulation; coupling; distance

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.

中枢神经系统中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的调节。在动作电位介导的突触前末端电压门控Ca 2+通道的去极化时，流入的Ca 2+通过结合囊泡释放传感器蛋白而触发突触活性区处的充满递质的突触囊泡（SV）的融合。Ca2+在明渠口周围形成一个陡峭的、短暂的浓度梯度，随着距离河道的增加而迅速减小。这使得通道和释放传感器之间的空间耦合距离成为突触传递功效的关键参数。迄今为止，已经区分了两种主要的耦合配置：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功效，特别是SV释放的高概率，而松耦合被认为提供更多的调节选择。耦合距离本身是如何调节的，目前还没有很好的理解。在所研究的突触中，已经描述了从松散的微结构域到紧密的纳米结构域耦合的发育转换，其显著改变了突触功效。突触效能进一步受到突触前长期可塑性的调节，同样是以年龄依赖性的方式。根据经典的可塑性规则，年轻皮层的突触偏向于长时程增强（LTP），而在成熟的突触中，LTP和长时程抑制（LTD）都被诱导。活动区地形和长期塑性之间的关系目前还很不清楚。在这个建议中，解决了以下假设：年轻的突触偏向LTP，因为他们有松散的微区耦合和收紧的耦合距离诱导优先，独立的可塑性协议的细节。成熟的突触以紧密的纳米域耦合操作，并且LTD增加耦合距离。LTP可能进一步加强成熟突触的耦合，但最有可能涉及进一步的机制，特别是招募额外的释放位点。该项目将活动区地形的年龄依赖性差异与长期塑性的年龄依赖性差异联系起来，从而确定活动区和长期塑性的过程和重排如何相互影响。由于释放和可塑性是神经元信息处理和皮层地图构建的核心，该项目解决了我们对大脑中突触成熟和编码的理解中的一个主要空白。