Neuronal-Glial Interaction in the Treatment of Bipolar Disorder

神经元-胶质细胞相互作用在双相情感障碍治疗中的作用

• 批准号: 8342146
• 负责人: MILES A. HERKENHAM
• 金额: $ 12.6万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8342146
• 关键词: AMPA Receptors; Behavioral; Bipolar Disorder; Brain; Cell surface; Complex; Data; Development; Dose; Functional disorder; Glutamate Receptor; Goals; Hippocampus (Brain); Hydroxyl Radical; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Isoxazoles; Lead; Learning; Light; Long-Term Effects; Major Depressive Disorder; Membrane; Memory; Molecular; Mood Disorders; Neurodegenerative Disorders; Neuroglia; Neuronal Plasticity; Neurons; Play; Propionates; Rattus; Regulation; Role; Stroke; Surface; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; Trauma; Traumatic Brain Injury; Tumor Necrosis Factor-alpha; cytokine; density; glutamate receptor subunit 3; human TNF protein; improved; neurotoxicity; novel; postsynaptic; response; synaptogenesis; trafficking

Pro-inflammatory cytokines, such as TNFalpha, IL-1, IL-6, were first discovered in the context of cellular activation and pro-inflammatory responses in the immune system. Early studies on the role of cytokines in the brain suggested that their expression and activity are induced in response to an infection, trauma, stroke, or neurodegenerative diseases. A growing body of data suggests that hyperactivation of the immune system has been implicated in the pathophysiology of major depressive disorder. Indeed, pro-inflammatory cytokines in the brain have been shown to regulate synaptic plasticity. TNFalpha, which is secreted from glial cells, regulates amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptor trafficking and neuroplasticity. In this study we investigated the long-term effect of TNFalpha on regulation of membrane expression of Glutamate Receptor 1 (GluR1), Glutamate Receptor 2 (GluR2) and Glutamate Receptor 3 (GluR3) AMPA receptor subunits. Rat primary hippocampal cultures were treated with various doses of TNFalpha for different periods of time. At the end of the treatment, changes in surface expression of AMPA receptor subunits were determined. Treatment of hippocampal neurons with TNFalpha increased expression of GluR1 subunit of AMPAR. TNFalpha had no effect on surface expression of GluR2 subunits. These findings suggest that TNFalpha-induced increase in AMPA receptors on the cell surface represents a novel molecular mechanism for neuron-glia interactions that might contribute to neurotoxicity in neuropathological conditions, associated with elevated levels of TNFalpha. We also found that treatment with TNFalpha at low doses for 1 day significantly enhanced the number of synapse and co-localization efficiency of GluR1 and the postsynaptic density marker PSD95 (post-synaptic density 95). This effect was sustained for up to 3 days. Together, these findings provide novel evidence that glial-derived TNFalpha promotes synaptogenesis in AMPA containing synapses, which might play a crucial role during traumatic brain injury, inflammation, and various psychiatric conditions.

促炎细胞因子，如TNF α、IL-1、IL-6，首先在免疫系统中的细胞活化和促炎反应的背景下被发现。 关于细胞因子在脑中的作用的早期研究表明，它们的表达和活性是响应于感染、创伤、中风或神经退行性疾病而被诱导的。 越来越多的数据表明，免疫系统的过度激活与重度抑郁症的病理生理学有关。 事实上，大脑中的促炎细胞因子已被证明可以调节突触可塑性。由神经胶质细胞分泌的TNF α调节氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）谷氨酸受体运输和神经可塑性。 在这项研究中，我们研究了TNF α对谷氨酸受体1（GluR 1）、谷氨酸受体2（GluR 2）和谷氨酸受体3（GluR 3）AMPA受体亚单位膜表达的长期调节作用。 用不同剂量的TNF α处理大鼠原代海马培养物不同的时间。在处理结束时，测定AMPA受体亚单位的表面表达的变化。用TNF α处理海马神经元增加AMPAR GluR 1亚单位的表达。 TNF α对GluR 2亚基的表面表达没有影响。这些发现表明，TNF α诱导的细胞表面AMPA受体增加代表了神经元-神经胶质相互作用的一种新的分子机制，可能导致神经病理学条件下的神经毒性，与TNF α水平升高相关。 我们还发现，用低剂量TNF α处理1天显著增加了突触数量和GluR 1和突触后密度标记物PSD 95（突触后密度95）的共定位效率。 这种效果持续了3天。总之，这些发现提供了新的证据，即胶质细胞衍生的TNF α促进含有AMPA的突触的突触发生，这可能在创伤性脑损伤，炎症和各种精神疾病中发挥关键作用。