Area-specific differences in cortical presynaptic coupling distances

大脑中的信息处理依赖于突触的传递和可塑性。动作电位打开突触前活动区的钙通道。钙的流入通过与囊泡释放感受器蛋白结合来触发突触小泡的融合。然而，钙离子浓度随着与通道距离的增加而迅速下降。这使得通道和小泡之间的空间耦合距离成为突触传递的保真度和可塑性的关键决定因素。到目前为止，已经区分了两种主要的耦合构型：紧密的纳米域耦合和松散的微域耦合。在成熟的大脑中，在不同的兴奋性突触上发现了紧密的耦合，这些突触具有高传输保真度，特别是传递频率编码感觉信息或周期性兴奋的突触。在这些突触，在出生后成熟期间，从松散耦合发展到紧密耦合。另一方面，在成熟的大脑中，在海马体中发现了高度可塑性的兴奋性突触的松散耦合。然而，这是否构成一般规则目前尚不清楚。特别是，尚不清楚在相同的主要类型的突触中，如果它们参与不同的功能，耦合距离和地形是否不同。新皮质或等皮质是一个形态相同的大脑区域，涵盖了高度不同的功能，从早期的感觉处理和运动控制到更高级别的联想和认知功能。值得注意的是，所有这些不同的功能都是由相同的神经元和突触原型执行的，尽管它们位于新皮质的不同区域。这里提出的假设是，如果相同主要类型的突触位于不同的皮质区域，则成熟新皮质中特定区域的功能差异与相同主要类型突触的功能突触前纳米结构的差异有关，甚至是由它们的差异引起的。具体地说，我认为参与低阶加工的皮质区域(如初级体感皮质)第2/3层和第5层的主要锥体神经元之间的突触以紧密的纳域耦合方式运作，这种紧密耦合是在出生后成熟期间发展起来的。另一方面，我认为相同的主要类型的突触即使在成熟的皮质中也是以松散的微域耦合方式运作的，如果它们位于参与更高级别处理的区域(例如前额叶皮质)。突触纳米拓扑学的这些差异将导致传递保真度和可塑性的特征差异。提案中的初步数据支持这一假设。我认为，对特定新皮质区域和层中相同突触原型之间的耦合距离的发育动力学进行比较，将对突触前结构-功能关系产生重要的新见解，甚至最终可能推导出这些关系的一般规则。

Information processing in the brain relies on synaptic transmission and plasticity. An action potential opens calcium channels at the presynaptic active zone. Inflowing calcium triggers the fusion of synaptic vesicles by binding to a vesicular release sensor protein. Yet, the calcium concentration rapidly decreases with increasing distance from the channel. This makes the spatial coupling distance between channels and vesicles a key determinant of the fidelity and plasticity of synaptic transmission. Two principle coupling configurations have been distinguished to date: tight nanodomain coupling and loose microdomain coupling. In the mature brain, tight coupling was found at different excitatory synapses with high transmission fidelity, in particular synapses transmitting frequency-coded sensory information or recurrent excitation. At these synapses, tight coupling developed from loose coupling during postnatal maturation. Loose coupling, on the other hand, was found in the mature brain at a highly plastic excitatory synapse in the hippocampus. However, whether this constitutes a general rule is currently unclear. In particular, it is unclear whether coupling distances and topographies differ at the same principal types of synapses if they are engaged in different functions. The neo- or isocortex is a morphologically homogeneous brain region that covers highly diverse functions, ranging from early sensory processing and motor control up to higher order associations and cognitive functions. Notably, all of these different functions are performed by the same archetypes of neurons and synapses albeit in different areas of the neocortex. Here, the hypothesis is put forth that area-specific functional differences in the mature neocortex are associated with or even arise from differences in the functional presynaptic nanoarchitecture of the same principal types of synapses if they are located in different cortical areas. Specifically, I propose that synapses between the principal pyramidal neurons in layers 2/3 and 5 in cortical areas engaged in lower order processing (e.g. primary somatosensory cortex) operate with tight nanodomain coupling and that this tight coupling develops during postnatal maturation. On the other hand, I propose that the same principal types of synapses operate with loose microdomain coupling even in the mature cortex if they are located in areas engaged in higher order processing (e.g. prefrontal cortex). These differences in the synaptic nanotopographies will give rise to characteristic differences in transfer fidelity and plasticity. Preliminary data in the proposal supports this hypothesis. I propose that a comparison of the developmental dynamics of coupling distances between the same archetypes of synapses in specific neocortical areas and layers will yield important novel insights into the presynaptic structure – function relationships and may ultimately even allow for deducing a general rule for these relationships.