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.

海马突触功能和学习记忆容易受到蛋白质O- GlcNAc化，β-N-乙酰葡糖胺（GlcNAc）与丝氨酸/苏氨酸（ser/thr）的O-连接 残基O-GlcNAc化现在被认为是认知功能障碍的可能治疗靶点， 特别是在阿尔茨海默病（AD）的治疗中，其中降低的O-GlcNAc可能允许 病理性tau过度磷酸化。全身给予OGA抑制剂Thiamet-G， 在转基因AD小鼠中增加tau磷酸化和改善空间学习和记忆。很显然， 确定O-GlcNAc酰化如何在生理和生理条件下调节神经元和突触功能， 病理生理条件对于了解其对学习和记忆的影响以及风险至关重要 和治疗干预的益处。 我们的实验室对这一新的研究领域做出了重大贡献， AMPAR GluA 2亚基O-GlcNAc酰化增加是在CA 3- CA 1突触（O-GlcNAc LTD），以及抑制癫痫发作模型中的病理性过度兴奋。我们 还发现O-GlcNAc的急性增加会干扰某些形式的依赖于海马的学习， 记忆因为记忆回路中的兴奋/抑制平衡控制着正常的学习和记忆， GABAAR的功能和运输通过丝氨酸磷酸化修饰，我们利用我们的专业知识， 研究在生理条件下发生的O-GlcNAc酰化的快速变化如何调节 GABA能抑制的功效。重要的是，因为不是所有的GABA能中间神经元都表达GluA 2亚基， O-GlcNAc LTD仅发生在中间神经元子集上的突触，这将改变电路 当O-GlcNAc酰化高时的动力学。在初步实验中，我们发现急剧增加的蛋白质 O-GlcNAc酰化降低sIPSC的振幅和频率以及记录的mIPSC的振幅 从大鼠海马脑片的CA 1锥体细胞。在这个探索性的建议，我们测试的假设，O- GlcNAc化通过突触后GABAAR和受体直接调节突触抑制的强度 内化，并间接通过在兴奋性突触上表达O-GlcNAc LTD， 具有含GluA 2的AMPAR的中间神经元。这些探索性研究的结果将建立一个 直接和间接控制GABA能抑制的全新基本机制， 为未来在神经退行性疾病中靶向O-GlcNAc的研究提供了框架， 阿尔茨海默氏病，以及神经发育障碍，如自闭症和唐氏综合症，其中 兴奋性和抑制性回路的不平衡是认知功能障碍的基础。这些研究的结果将 在一个尚处于起步阶段的领域取得了巨大的进步。