A novel function for Wnt signaling modulating neuronal firing activity and the temporal structure of spontaneous oscillation in the entorhinal-hippocampal circuit
A novel function for Wnt signaling modulating neuronal firing activity and the temporal structure of spontaneous oscillation in the entorhinal-hippocampal circuit
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DOI：
10.1016/j.expneurol.2015.03.027
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发表时间：
2015-07-01
影响因子：
5.3
通讯作者：
Inestrosa, Nibaldo C.
中科院分区：
文献类型：
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作者：
Oliva, Carolina A.;Inestrosa, Nibaldo C.
在出生后的早期和晚期发育过程中，功能性神经元连接的建立取决于像Wnt这样的分子，这些分子帮助最近形成的突触建立和巩固它们新的细胞相互作用。然而，与其他分子不同，Wnt是否可以调节细胞的放电特性尚不清楚。在这里，我们第一次探索的典型和非典型的Wnt通路上的电路，目前正在产生振荡活动，内嗅皮层-海马电路的生理效应。我们的结果表明，Wnt通路对回路和细胞性质具有强烈的影响，这取决于Wnt蛋白亚型、浓度和神经元回路的类型。针对典型和非典型配体以及WASP-1和sFRP-2的抗体表明，Wnt的组成性释放有助于维持网络和回路的内在性质。此外，我们发现，过量的Wnt 3a或用BIO-6对通路的永久细胞内激活通过破坏短单位中的振荡单位（Up状态）而加速振荡周期，推测是通过影响将神经元耦合到振荡周期中的突触机制，但不影响尖峰产生。相反，低剂量的Wnt 5a通过将新细胞纳入网络活动来增加EC中的振荡周期，可能修改电路其他地方的放电活动。此外，我们发现Wnt信号在海马中根据不同的原则运作。利用双羟萘酸吡咯烷铵（pyrvinium pamoate），一种Wnt/β-catenin依赖性通路抑制剂，我们证明了该通路对于维持CA 3回路的放电活性是必不可少的，并且在较低程度上维持CA 1回路的放电活性。然而，CA 1回路具有自稳态机制，当CA 3回路的放电活性被抑制时，该通路上调放电活性，并且当加剧的回路活性占主导地位时，该通路下调细胞的兴奋性。总之，释放的Wnt的量可以对生理输出进行微调，调节放电活动，提高神经元之间通信的可靠性，并维持突触结构-功能的连续自我调节周期，这些周期可以存在于所有出生后的生活中。(C)2015 Elsevier Inc. All rights reserved.
During early and late postnatal developments, the establishment of functional neuronal connectivity depends on molecules like Wnt that help the recently formed synapses to establish and consolidate their new cellular interactions. However, unlike other molecules, whether Wnt can modulate the firing properties of cells is unknown. Here, for the first time we explore the physiological effect of the canonical and non-canonical Wnt pathways on a circuit that is currently generating oscillatory activity, the entorhinal cortex-hippocampal circuit. Our results indicate that Wnt pathways have strong influence in the circuital and cellular properties depending on the Wnt protein isoforms, concentration, and type of neuronal circuit Antibodies against canonical and non-canonical ligands, as well as WASP-1 and sFRP-2, demonstrate that constitutive release of Wnts contributes to the maintenance of the network and intrinsic properties of the circuit Furthermore, we found that the excess of Wnt3a or the permanent intracellular activation of the pathway with BIO-6 accelerates the period of the oscillation by disrupting the oscillatory units (Up states) in short units, presumably by affecting the synaptic mechanisms that couples neurons into the oscillatory cycle, but without affecting the spike generation. Instead, low doses of Wnt5a increase the period of the oscillation in EC by incorporating new cells into the network activity, probably modifying firing activity in other places of the circuit Moreover, we found that Wnt signaling operates under different principles in the hippocampus. Using pyrvinium pamoate, a Wnt/beta-catenin dependent pathway inhibitor, we demonstrated that this pathway is essential to keep the firing activity in the circuit CA3, and in less degree of CA1 circuit However, CA1 circuit possesses homeostatic mechanisms to up-regulate the firing activity when it has been suppressed in CA3, and to down-modulate the cellular excitability when exacerbated circuital activity has dominated. In summary, the amount of Wnt that is being released can exert a fine tuning of the physiological output, modulating firing activity, improving reliability of communication between neurons, and maintaining a continuous self-regulatory cycle of synaptic structure-function that can be present during all postnatal life. (C) 2015 Elsevier Inc. All rights reserved.