L-type Ca2+ Channel Spike Regulation of Spine Structural Plasticity and Excitation-Transcription Coupling

海马区的可塑性导致突触结构和功能的持续变化 学习和记忆是基础。激活NMDA受体下游的细胞内钙信号通路 (NMDAR)和L型电压门控钙通道(LTCC)参与改变突触功能 可塑性的初始表达以及支持长期的基因表达的变化所需的 保持可塑性。尤其是LTCCs的激活在树突棘结构中起着关键作用。 可塑性和激发-转录(E-T)耦合控制核内转录因子的活性， 如cAMP/钙反应元件结合蛋白(CREB)，活化T细胞核因子(NFAT)，以及 心肌细胞增强因子2(MEF2)。LTCC功能的改变与多种神经和 神经精神疾病。重要的是，NFAT依赖的转录可能控制一些基因的表达 在调节E/I平衡和兴奋性方面起关键作用的靶基因包括GABAA-Rs和电压门控钾(Kv)通道。我们之前的工作建立了支架蛋白AKAP79/150，它 将cAMP依赖的激酶PKA和钙依赖的磷酸酶钙调神经磷酸酶(CaN)锚定在 LTCCs通过CaN介导的NFAT去磷酸化，作为E-T偶联的重要调节因子。然而， 由于树突中的突触和胞体中的核之间的距离很远，神经元面临着独特的 将突触输入转换为控制转录的生化信号的挑战。我们最近发现 LTP刺激NMDAR-LTCC-NFAT突触到核的信号转导利用树突状钙峰 传播到SOMA作为一种新的E-T耦合机制。另外，我们发现这个<English>NMDAR</English><English>LTCC</English> LTP诱导过程中的激活促进了钙诱导的树突中钙的释放，从而参与了 内质网钙传感器STIM1触发LTCC钙内流的负反馈调节 同时还调节树突内质网的新结构可塑性。然而，在以下方面仍存在严重差距 我们关于NMDAR、LTCC和STIM1如何在不同的空间和时间尺度上运行的知识 既控制局部树突结构可塑性，又控制远端树枝到胞体的穗状花序繁殖来调节 抄写。此外，我们还不了解特定活性调控靶基因的转录是如何 基因由不同的活动模式控制，这些活动模式通过这些机制来调节关键方面 神经功能，如E/I平衡。因此，在这里，我们建议进行研究，通过表征来填补这些空白 突触后LTCC钙信号在树突和钙峰局部结构可塑性中的作用 NFAT及其共调控因子调控基因表达的树突至胞体传递(Aim 1) 影响E/I平衡(目标2)。

Plasticity in the hippocampus leads to persistent changes in synaptic structure and function that underlie learning and memory. Intracellular Ca2+ signaling pathways activated downstream of NMDA receptors (NMDAR) and L-type voltage-gated Ca2+ channels (LTCC) contribute to changes synaptic function that are required for initial expression of plasticity as well as changes in gene expression that support long-term maintenance of plasticity. In particular, activation of LTCCs plays a key role in dendritic spine structural plasticity and excitation-transcription (E-T) coupling to control the activity of transcription factors in the nucleus, such as cAMP/Ca2+-response element binding protein (CREB), nuclear factor of activated T-cells (NFAT), and myocyte enhancer factor 2 (MEF2). Alterations in LTCC function have been linked to multiple neurological and neuropsychiatric diseases. Importantly, NFAT-dependent transcription may control the expression of a number of target genes that play key roles in regulating E/I balance and excitability, including GABAA-Rs and voltage-gated potassium (Kv) channels. Our previous work established the scaffold protein AKAP79/150, which anchors the cAMP-dependent kinase PKA and the Ca2+-dependent phosphatase calcineurin (CaN) near LTCCs, as an essential regulator of E-T coupling via CaN-mediated dephosphorylation of NFAT. However, due to the large distances between synapses in dendrites and the nucleus in the soma, neurons face unique challenges in converting synaptic input into biochemical signals that control transcription. We recently found that LTP stimulated NMDAR-LTCC-NFAT synapse-to-nucleus signaling utilizes dendritic Ca2+ spike propagation to the soma as a novel E-T coupling mechanism. In addition, we found that this NMDAR-LTCC activation during LTP induction promotes Ca2+-induced Ca2+ release in dendrites that engages the endoplasmic reticulum (ER) Ca2+ sensor STIM1 to trigger negative-feedback regulation of LTCC Ca2+ influx while also mediating novel structural plasticity of the dendritic spine ER. However, there are still critical gaps in our knowledge regarding how NMDARs, LTCCs, and STIM1 operate over different spatial and temporal scales to control both local dendritic structural plasticity and distal dendrite-to-soma spike propagation to regulate transcription. Furthermore, we do not understand how the transcription of specific activity-regulated target genes is controlled by different patterns of activity transduced by these mechanisms to modulate key aspects of neuronal function, such as E/I balance. Thus, here we propose research to fill these gaps by characterizing the roles of postsynaptic LTCC Ca2+ signaling in mediating local structural plasticity in dendrites and Ca2+ spike relay from dendrites to soma (aim 1) in control gene of expression through NFAT and its co-regulators to impact E/I balance (aim 2).