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).

海马中的可塑性导致突触结构和功能的持续变化 学习和记忆的基础。细胞内Ca2+信号通路激活了NMDA受体的下游 （NMDAR）和L型电压门控CA2+通道（LTCC）有助于变化突触功能 最初表达可塑性以及支持长期的基因表达的变化所必需的 维持可塑性。特别是，LTCC的激活在树突状脊柱结构中起关键作用 可塑性和激发转录（E-T）耦合以控制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（NFAT）的核因子，而 心肌细胞增强子因子2（MEF2）。 LTCC功能的改变已与多个神经系统相关 神经精神疾病。重要的是，依赖NFAT的转录可以控制数字的表达 在调节E/I平衡和兴奋性方面起关键作用的目标基因，包括GABAA-RS和电压门控钾（KV）通道。我们以前的工作建立了脚手架蛋白AKAP79/150， 锚定cAMP依赖性激酶PKA和Ca2+依赖性磷酸酶钙调神经酶（CAN）附近 LTCCS，作为E-T偶联的必不可少的调节剂，通过CAN介导的NFAT的去磷酸化。然而， 由于树突中的突触与躯体中的核之间的距离很大，神经元面临独特的 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突触到核核信号传导利用了树突状CA2+ Spike 作为一种新型的E-E-t耦合机制传播到SOMA。此外，我们发现此NMDAR-LTCC LTP诱导期间的激活促进Ca2+诱导的Ca2+释放的树突中的Ca2+释放 内质网（ER）Ca2+传感器stim1触发LTCC CA2+流入的负反馈调节 同时还介导树突状脊柱ER的新型结构可塑性。但是，仍然存在关键的差距 我们关于NMDAR，LTCC和STIM1如何在不同的空间和时间尺度上运作的知识 控制局部树突状结构可塑性和远端树突向菌群尖峰传播以调节 转录。此外，我们不了解特定活性调节目标的转录 基因由这些机制转导的不同活性模式控制，以调节关键方面 神经元功能，例如E/I平衡。因此，在这里，我们提出研究以填补这些空白来通过表征来填补这些空白 突触后LTCC Ca2+信号传导在介导的树突和Ca2+尖峰中的局部结构可塑性中的作用 通过NFAT及其共同调节剂从树突转移到SOMA（目标1）（目标1） 影响E/I平衡（AIM 2）。