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

脊柱结构可塑性和兴奋转录耦合的 L 型 Ca2 通道尖峰调节

• 批准号: 10209537
• 负责人: MARK L DELL'ACQUA
• 金额: $ 59.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209537
• 关键词: A kinase anchoring protein; Alzheimer' s Disease; Attention deficit hyperactivity disorder; Binding Proteins; Biochemical; Bipolar Disorder; Brain; Calcineurin; Calcium Channel; Calcium ion; Cell Nucleus; Complex; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dendrites; Dendritic Spines; Distal; Down Syndrome; Endoplasmic Reticulum; Equilibrium; Excitatory Synapse; Face; Feedback; Gene Expression; Genes; Genetic Transcription; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Impaired cognition; Intellectual functioning disability; Knowledge; Lead; Learning; Link; Long-Term Potentiation; Maintenance; Major Depressive Disorder; Mediating; Memory; Mental Depression; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Potassium; Process; Protein Dephosphorylation; Protein Kinase; Receptor Activation; Regulation; Research; Response Elements; Rodent; Role; STIM1 gene; Scaffolding Protein; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Synapses; Synaptic plasticity; Transcription Factor AP-1; Transcriptional Regulation; Vertebral column; Work; autism spectrum disorder; calcineurin phosphatase; myocyte-specific enhancer-binding factor 2; nervous system disorder; neuronal cell body; neuropsychiatric disorder; novel; nuclear factors of activated T-cells; postsynaptic; receptor; response; sensor; synaptic function; transcription factor; voltage

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).

海马体的可塑性导致突触结构和功能的持续变化， 是学习和记忆的基础。 NMDA 受体下游激活细胞内 Ca2+ 信号通路 (NMDAR) 和 L 型电压门控 Ca2+ 通道 (LTCC) 有助于改变突触功能， 可塑性的初始表达以及支持长期的基因表达变化所需 维持可塑性。特别是，LTCC 的激活在树突棘结构中起着关键作用。 可塑性和兴奋转录（E-T）耦合来控制细胞核中转录因子的活性， 例如 cAMP/Ca2+ 反应元件结合蛋白 (CREB)、活化 T 细胞核因子 (NFAT) 和 肌细胞增强因子 2 (MEF2)。 LTCC 功能的改变与多种神经系统和 神经精神疾病。重要的是，NFAT 依赖性转录可能控制许多基因的表达 在调节 E/I 平衡和兴奋性中发挥关键作用的靶基因，包括 GABAA-R 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， 将 cAMP 依赖性激酶 PKA 和 Ca2+ 依赖性磷酸酶钙调神经磷酸酶 (CaN) 锚定在附近 LTCC，通过 CaN 介导的 NFAT 去磷酸化，作为 E-T 耦合的重要调节剂。然而， 由于树突中的突触与体细胞中的细胞核之间的距离较大，神经元面临着独特的 将突触输入转化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 突触到细胞核信号传导利用树突状 Ca2+ 尖峰 作为一种新颖的 E-T 耦合机制传播到体细胞。另外，我们发现这个NMDAR-LTCC LTP 诱导期间的激活促进树突中 Ca2+ 诱导的 Ca2+ 释放，从而参与 内质网 (ER) Ca2+ 传感器 STIM1 触发 LTCC Ca2+ 流入的负反馈调节 同时还介导树突棘 ER 的新颖结构可塑性。然而，仍然存在关键差距 我们关于 NMDAR、LTCC 和 STIM1 如何在不同空间和时间尺度上运行的知识 控制局部树突结构可塑性和远端树突到体细胞的尖峰传播以调节 转录。此外，我们不明白特定活性调节靶标的转录是如何进行的 基因由这些机制转导的不同活动模式控制，以调节关键方面 神经元功能，例如 E/I 平衡。因此，我们在这里提出研究，通过表征来填补这些空白 突触后 LTCC Ca2+ 信号在介导树突局部结构可塑性和 Ca2+ 尖峰中的作用 通过 NFAT 及其协同调节器从树突到体细胞（目标 1）控制表达基因的中继 影响 E/I 平衡（目标 2）。