Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.
Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy.
Cereb Cortex. 2019 May 1;29(5):1851-1865. doi: 10.1093/cercor/bhy042.
Spike timing-dependent plasticity (STDP) is a form of activity-dependent remodeling of synaptic strength that underlies memory formation. Despite its key role in dictating learning rules in the brain circuits, the molecular mechanisms mediating STDP are still poorly understood. Here, we show that spike timing-dependent long-term depression (tLTD) and A-type K+ currents are modulated by pharmacological agents affecting the levels of active glycogen-synthase kinase 3 (GSK3) and by GSK3β knockdown in layer 2/3 of the mouse somatosensory cortex. Moreover, the blockade of A-type K+ currents mimics the effects of GSK3 up-regulation on tLTD and occludes further changes in synaptic strength. Pharmacological, immunohistochemical and biochemical experiments revealed that GSK3β influence over tLTD induction is mediated by direct phosphorylation at Ser-616 of the Kv4.2 subunit, a molecular determinant of A-type K+ currents. Collectively, these results identify the functional interaction between GSK3β and Kv4.2 channel as a novel mechanism for tLTD modulation providing exciting insight into the understanding of GSK3β role in synaptic plasticity.
译文：
标题： 突触传递效能变化的长时程抑制（tLTD）受调控于活性糖原合成酶激酶 3（GSK3）水平以及 A 型钾通道电流
摘要： 突触传递效能变化的长时程抑制（tLTD）是一种依赖于活动的突触强度重塑形式，是记忆形成的基础。尽管其在大脑回路中决定学习规则方面发挥着关键作用，但介导 tLTD 的分子机制仍知之甚少。在这里，我们发现，通过影响活性糖原合成酶激酶 3（GSK3）水平的药理学制剂以及通过在小鼠体感皮层的 2/3 层敲低 GSK3β，可调节突触时程依赖性长时程抑制（tLTD）和 A 型钾电流。此外，A 型钾电流的阻断可模拟 GSK3 上调对 tLTD 的影响，并阻断突触强度的进一步变化。药理学、免疫组织化学和生化实验表明，GSK3β 对 tLTD 诱导的影响是通过直接磷酸化 Kv4.2 亚基的丝氨酸 616 介导的，该亚基是 A 型钾电流的分子决定因素。总的来说，这些结果确定了 GSK3β 与 Kv4.2 通道之间的功能相互作用作为 tLTD 调节的一种新机制，为理解 GSK3β 在突触可塑性中的作用提供了令人兴奋的见解。
