MARK1 in dendritic spine neoteny

树突棘幼态持续中的 MARK1

• 批准号: 10753728
• 负责人: Huaye Zhang
• 金额: $ 40.12万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753728
• 关键词: AMPA Receptors; Acceleration; Adult; Affect; Affinity; Antibodies; Biochemical; Biological Assay; Biosensor; Biotinylation; Bipolar Disorder; Brain; C-terminal; Complement; DLG4 gene; Data; Dendritic Spines; Development; Evolution; Fluorescence Resonance Energy Transfer; Genes; GluR2 subunit AMPA receptor; Glutamates; Hippocampus; Human; Image; Impairment; Knowledge; Learning; Length; Link; Mediating; Memory; Microtubules; Molecular; Molecular Conformation; Morphology; Mus; Neurodevelopmental Disorder; Neurons; PHluorin; Phosphorylation; Phosphotransferases; Prosencephalon; Reporting; Rodent; Role; Scaffolding Protein; Single Nucleotide Polymorphism; Site; Stimulus; Surface; Synapses; Testing; Time; Vertebral column; autism spectrum disorder; cognitive capacity; cognitive function; cognitive performance; density; experimental study; hippocampal pyramidal neuron; imaging approach; nano; nanocluster; optogenetics; premature; pressure; scaffold; spatiotemporal; superresolution imaging; tau Proteins; trafficking; two-photon; uptake

Project Summary A key cellular substrate underlying learning and memory is the plasticity of dendritic spines, which are sites of excitatory synaptic inputs in the mammalian brain. Dendritic spines show protracted synaptic maturation during human brain development, leading to longer spines with higher density in adulthood as compared with rodents. This extraordinary neoteny of spines is believed to underlie the high cognitive performance in humans. However, there remains a dearth of knowledge regarding the molecular mechanisms that contribute to dendritic spine neoteny unique to humans. One way to approach this issue is to examine genes that show adaptive evolution along the human lineage. These genes are under positive selection pressure and are likely to play a role in human speciation. In particular, genes that show adaptive evolution and genetically linked to neurodevelopmental disorders are strong candidates that may contribute to the high cognitive capacity of the human brain. To date, there are only a handful of genes reported to fit both criteria. One of the genes encodes the Microtubule Affinity Regulating Kinase 1 (MARK1), a Ser/Thr kinase highly expressed in the brain. MARK1 displays strong evidence of adaptive evolution in the lineage leading to humans, and single nucleotide polymorphisms (SNPs) of MARK1 are associated with autism spectrum disorders (ASD) and bipolar disorder. We previously found MARK-mediated phosphorylation of the synaptic scaffolding protein PSD-95 is important for bidirectional dendritic spine plasticity. Moreover, our preliminary studies show loss of MARK1 in forebrain pyramidal neurons leads to reduced spine formation and delayed spatial learning. In addition, we observed a significant increase in the synaptic levels of the AMPA receptor subunit GluR2 in the MARK1 conditional KO (cKO) hippocampus. By contrast, in neurons where rodent MARK1 was replaced with human MARK1, we observed increased spine density and immature morphology reminiscent of human neurons. These exciting data led us to hypothesize that loss of MARK1 leads to premature dendritic spine stabilization, which limits spine density and impairs learning. Conversely, human MARK1 shows enhanced kinase activity leading to dendritic spine neoteny and increased spine density, which contributes to high cognitive functions in humans. Aim 1 will test the hypothesis that human MARK1 contributes to spine neoteny through regulating the PSD scaffold and GluR2 trafficking. Aim 2 will test the hypothesis that altered spatiotemporal dynamics of human MARK1 activity is responsible for its effects on spine neoteny. We will utilize FRET, FRAP, super resolution imaging, and two- photon glutamate uncaging. We will complement these imaging approaches with biochemical analyses and optogenetic manipulation of MARK1 activity. Completion of the proposed experiments will establish a role for MARK1 in dendritic spine neoteny observed in human neurons. The results can shed light on the molecular mechanisms underlying high level cognitive functions of the human brain.

项目概要 学习和记忆的关键细胞基质是树突棘的可塑性，树突棘是 哺乳动物大脑中兴奋性突触输入的位点。树突棘显示突触延长 在人类大脑发育过程中成熟，导致成年后脊柱更长、密度更高 与啮齿类动物相比。脊柱的这种非凡的幼态持续被认为是高认知能力的基础 在人类中的表现。然而，人们对分子生物学的认识仍然缺乏。 导致人类独特的树突棘幼态持续的机制。解决这个问题的一种方法 问题是检查沿着人类谱系显示适应性进化的基因。这些基因处于 正选择压力并可能在人类物种形成中发挥作用。特别是，基因显示 适应性进化和与神经发育障碍有关的遗传因素是可能的有力候选者 有助于人类大脑的高认知能力。迄今为止，只有少数基因 据报道符合这两个标准。其中一个基因编码微管亲和力调节激酶 1 (MARK1)，一种 Ser/Thr 激酶在大脑中高度表达。 MARK1显示出适应性进化的有力证据 MARK1 的单核苷酸多态性 (SNP) 与自闭症相关 谱系障碍（ASD）和双相情感障碍。我们之前发现 MARK 介导的磷酸化 突触支架蛋白 PSD-95 对于双向树突棘可塑性非常重要。此外，我们的 初步研究表明，前脑锥体神经元中 MARK1 的缺失会导致脊柱形成减少， 延迟空间学习。此外，我们观察到 AMPA 的突触水平显着增加 MARK1 条件性 KO (cKO) 海马中的受体亚基 GluR2。相比之下，在神经元中 啮齿动物 MARK1 被人类 MARK1 取代，我们观察到脊柱密度增加且不成熟 形态让人想起人类神经元。这些令人兴奋的数据使我们推测 MARK1 的丢失 导致树突棘过早稳定，从而限制树突棘密度并损害学习。 相反，人类 MARK1 显示出增强的激酶活性，导致树突棘幼态持续和 脊柱密度增加，有助于人类的高认知功能。目标 1 将测试 假设人类 MARK1 通过调节 PSD 支架和 GluR2 促进脊柱幼态持续 贩运。目标 2 将检验以下假设：人类 MARK1 活性的时空动态变化是 负责其对脊柱幼态持续的影响。我们将利用 FRET、FRAP、超分辨率成像和两 光子谷氨酸解禁。我们将通过生化分析来补充这些成像方法 MARK1 活性的光遗传学操作。完成拟议的实验将确立以下角色： 在人类神经元中观察到的树突棘幼态持续状态中的 MARK1。结果可以揭示分子 人脑高级认知功能的机制。