Rapid modulation of hippocampal GABAergic Inhibition by O-GlcNAcylation

海马区突触功能和学习记忆易受O-蛋白改变的影响 GlcN酰化，β-N-乙酰氨基葡萄糖(GlcNAc)与丝氨酸/苏氨酸(Ser/Thr)的O-连接 残留物。O-GlcN酰化现在被认为是认知功能障碍的可能治疗靶点， 尤其是在阿尔茨海默病(AD)的治疗中，O-GlcNAc的降低可能允许 病理性tau蛋白过度磷酸化。全身应用OGA抑制剂硫代蛋氨酸-G可逆转 在转基因AD小鼠中tau磷酸化增加和改善空间学习和记忆。显然， 生理和病理状态下O-GlcN酰化对神经元和突触功能的调节作用 病理生理条件对于了解其对学习和记忆的影响及其风险是至关重要的。 以及治疗干预的好处。 我们的实验室在这一新的研究领域做出了重大贡献，表明了急性和选择性 AMPAR GluA2亚基O-GlcN酰化的增加是一种新形式的LTD在CA3- CA1突触(O-GlcNAc Ltd.)，以及抑制癫痫模型的病理性高兴奋性。我们 还发现O-GlcNAc的急剧增加干扰了某些形式的海马体依赖的学习和 记忆。因为记忆电路中的兴奋/抑制平衡控制着正常的学习和记忆，并且 GABAAR的功能和运输是通过丝氨酸磷酸化修饰的，我们已经利用我们的专业知识 研究生理条件下O-GlcN酰化的快速变化如何调节 GABA能抑制的疗效。重要的是，因为并不是所有的GABA能中间神经元都表达GluA2亚单位， O-GlcNAc LTD将只出现在部分中间神经元的谷氨酸能突触上，这将改变电路 当O-GlcN酰化程度较高时的动力学。在初步实验中，我们发现蛋白质急剧增加 O-GlcN酰化降低sIPSCs的幅度和频率以及记录的mIPSCs的幅度 来自大鼠海马片中的CA1锥体细胞。在这个探索性的提案中，我们测试了O- GlcN酰化通过突触后GABA受体直接调节突触抑制强度 内化，并间接通过O-GlcNAc Ltd在兴奋性突触表达到特定的 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一个 直接和间接控制GABA能抑制的全新基本机制，从而 为未来针对O-GlcNAc在神经退行性疾病中的研究提供一个框架，例如 阿尔茨海默氏症，以及自闭症和唐氏综合症等神经发育障碍，其中 兴奋性和抑制性回路的失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巨大进步。

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.