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: 10380180
• 负责人: MARK L DELL'ACQUA
• 金额: $ 53.73万
• 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/10380180
• 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