Rapid modulation of hippocampal GABAergic Inhibition by O-GlcNAcylation

O-GlcNAc 酰化快速调节海马 GABA 能抑制

• 批准号: 9765783
• 负责人: JOHN C CHATHAM
• 金额: $ 40.84万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765783
• 关键词: Acute; Alzheimer' s Disease; Area; Benefits and Risks; Brain; Brain Diseases; Chronic; Cognition; Cognitive; Data; Disease; Down Syndrome; Drug Industry; Effectiveness; Endocytosis; Enzymes; Equilibrium; Excision; Excitatory Synapse; Frequencies; Future; Genetic; Global Change; Glucose; Glutamates; Health; Hexosamines; Hippocampus (Brain); Impaired cognition; In Vitro; Interneurons; Knockout Mice; Learning; Link; Literature; Mediating; Memory; Mental Depression; Metabolic; Modeling; Modification; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; O-GlcNAc transferase; Pathologic; Pathology; Pathway interactions; Pharmacology; Phosphorylation; Physiological; Physiology; Post-Translational Protein Processing; Proteins; Pyramidal Cells; Rattus; Regulation; Research; Role; Seizures; Serine; Slice; Synapses; Synaptic Membranes; Testing; Therapeutic; Therapeutic Intervention; Threonine; Transgenic Mice; Transgenic Organisms; autism spectrum disorder; behavioral study; experimental study; improved; in vivo; infancy; inhibitor/antagonist; interest; neural circuit; novel; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; postsynaptic; receptor; receptor internalization; synaptic function; synaptic inhibition; tau Proteins; tau aggregation; tau phosphorylation; therapeutic target; trafficking; transmission process

Hippocampal synaptic function and learning and memory are vulnerable to alterations in protein O- GlcNAcylation, the O-linked attachment of β-N-acetylglucosamine (GlcNAc) to serine/threonine (ser/thr) residues. O-GlcNAcylation is now recognized as a possible therapeutic target for cognitive dysfunction, particularly in the treatment of Alzheimer's disease (AD), where decreased O-GlcNAc may be permissive for pathological tau hyperphosphorylation. Systemic administration of the OGA inhibitor, thiamet-G, reversed the increase in tau phosphorylation and improved spatial learning and memory in transgenic AD mice. Obviously, determining how O-GlcNAcylation modulates neuronal and synaptic function under physiological and pathophysiological conditions is imperative to understanding its impact on learning and memory, and the risks and benefits of therapeutic intervention. Our lab has made significant contributions to this new area of research by showing that acute and selective increase in O-GlcNAcylation of AMPAR GluA2 subunits underlies expression of a novel form of LTD at CA3- CA1 synapses (O-GlcNAc LTD), as well as the dampening pathological hyperexcitability in seizure models. We also find that acute increases in O-GlcNAc interferes with some forms of hippocampus-dependent learning and memory. Because excitation/inhibition balance in memory circuits governs normal learning and memory, and GABAAR function and trafficking is modified by serine phosphorylation, we have used our expertise to investigate how rapid changes in O-GlcNAcylation occurring under physiological conditions modulates the efficacy of GABAergic inhibition. Importantly, because not all GABAergic interneurons express GluA2 subunits, O-GlcNAc LTD will only occur at glutamatergic synapses on a subset of interneurons, which will alter circuit dynamics when O-GlcNAcylation is high. In preliminary experiments, we found that acutely increasing protein O-GlcNAcylation decreases the amplitude and frequency of sIPSCs and the amplitude of mIPSCs recorded from CA1 pyramidal cells in rat hippocampal slices. In this exploratory proposal, we test the hypothesis that O- GlcNAcylation directly modulates the strength of synaptic inhibition via postsynaptic GABAARs and receptor internalization, and indirectly via expression of O-GlcNAc LTD at excitatory synapses onto specific interneurons possessing GluA2-containing AMPARs. The results of these exploratory studies will establish an entirely novel fundamental mechanism that directly and indirectly controls GABAergic inhibition, thereby providing a framework for future studies targeting O-GlcNAc in neurodegenerative diseases, such as Alzheimer's disease, and in neurodevelopmental disorders such as autism and Down syndrome, where imbalances in excitatory and inhibitory circuits underlie cognitive dysfunction. The results of these studies will make a huge advance in a field that is in its infancy.

海马突触功能，学习和记忆容易受到蛋白质O-的改变 Glcnacylation，β-N-乙酰葡萄糖（GlcNAC）与丝氨酸/苏氨酸（Ser/Thr）的O连接附着 残留物。现在，O-Glcnacylation被认为是认知功能障碍的可能的治疗靶点， 特别是在治疗阿尔茨海默氏病（AD）中，改善O-GLCNAC可能是允许的 病理tau高磷酸化。 OGA抑制剂的系统性给药，thiamet-g逆转了 转基因AD小鼠中TAU磷酸化的增加，并改善了空间学习和记忆。明显地， 确定O-Glcnacylation如何在生理和 病理生理状况必须了解其对学习和记忆的影响以及风险 和治疗干预的好处。 我们的实验室通过表明急性和选择性为这一新的研究领域做出了重大贡献 AMPAR GLUA2亚基的O-Glcnacylation的增加是CA3-的新型LTD表达 CA1突触（O-GLCNAC LTD），以及癫痫发作模型中的衰减病理过度兴奋性。我们 还发现O-GLCNAC干扰某些形式的海马依赖性学习和 记忆。因为记忆电路中的兴奋/抑制平衡控制正常的学习和记忆，并且 Gabaar功能和贩运是通过丝氨酸磷酸化来修改的，我们已经使用我们的专业知识来 研究在生理条件下O-Glcnacylation的快速变化如何调节 GABA能抑制的有效性。重要的是，因为并非所有GABA能中间神经元表达GLUA2亚基，所以 O-GLCNAC LTD仅在中间神经元的子集的谷氨酸能突触上发生，该突触将改变电路 当O-Glcnacylation高时动力学。在初步实验中，我们发现蛋白质急性增加 O-GlcNacylation降低了SIPSC的放大器和频率，并记录了MIPSC的放大器 来自大鼠海马切片中的CA1锥体细胞。在这项探索性建议中，我们检验了O-的假设 Glcnacylation直接通过突触后Gabaar和接收器调节突触抑制的强度 内在化，并通过在兴奋性突触上的O-GLCNAC LTD的表达间接地表达在特定上 具有含GLUA2的AMPAR的中间神经元。这些探索性研究的结果将建立 完全新颖的基本机制直接和间接控制GABA能抑制，从而 为针对神经退行性疾病的O-GLCNAC的未来研究提供了一个框架，例如 阿尔茨海默氏病，以及在自闭症和唐氏综合症等神经发育障碍中 兴奋和抑制回路的失衡是认知功能障碍的基础。这些研究的结果将 在起步阶段的领域中取得了巨大进步。