Neuronal-Glial Interaction in the Treatment of Bipolar Disorder

促炎细胞因子，如肿瘤坏死因子α、白介素1和白介素6，首先在免疫系统的细胞反应的背景下被研究。对细胞因子在大脑中作用的研究表明，它们的表达和活性是在感染、创伤、中风或神经退行性疾病的反应中诱导的。越来越多的数据表明，中枢神经系统中免疫相关细胞因子的激活可能参与了严重抑郁障碍的病理生理学。事实上，促炎细胞因子已被证明可以调节突触的可塑性。肿瘤坏死因子α主要由小胶质细胞分泌，在急性给药时调节amino-3-hydroxyl-5-methyl-4-isoxazole-propionate(AMPA)谷氨酸受体的转运和神经可塑性。在本研究中，我们观察了长期应用肿瘤坏死因子α对谷氨酸受体1(GluR1)、谷氨酸受体2(GluR2)和谷氨酸受体3(GluR3)AMPA受体亚单位膜表达的调节作用。用不同剂量的肿瘤坏死因子α处理原代培养的大鼠海马区不同时间。治疗结束后，检测AMPA受体亚基表面表达的变化。肿瘤坏死因子α可增加AMPAR GluR1亚基的表达水平，但对GluR2亚基的表面表达无影响。这些发现表明，肿瘤坏死因子α诱导的细胞表面AMPA受体的增加代表了神经元-神经胶质细胞相互作用的一种新的分子机制，这种机制可能导致神经病理条件下的神经毒性，与肿瘤坏死因子α水平的升高相关。 我们还发现，低剂量的TNFpha处理1d，显著增加了突触数量和GluR1的共定位效率，以及突触后密度标记PSD95(突触后密度95)。这一影响持续了长达3天。 在活体动物研究中，小鼠第三脑室注射低剂量的肿瘤坏死因子α可增强旷场和高架迷宫试验中的抗焦虑行为；然而，高剂量的肿瘤坏死因子α则表现出抑制作用。综上所述，这些结果表明，在培养的海马神经元中，肿瘤坏死因子α诱导的突触发生在倒U形的方式中，并对焦虑缓解行为的动物模型具有类似的影响。我们的发现提供了新的证据，表明肿瘤坏死因子α调节突触发生，这可能在创伤性脑损伤、炎症和精神疾病中发挥关键作用。

Pro-inflammatory cytokines such as TNFalpha, IL-1, and IL-6, were first studied in the context of cellular responses in the immune system. 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 immune-related cytokine activation in the CNS may contribute to the pathophysiology of major depressive disorder. Indeed, pro-inflammatory cytokines have been shown to regulate synaptic plasticity. TNFalpha, which is secreted mainly from microglial cells, regulates amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptor trafficking and neuroplasticity when administered acutely. In this study we investigated the long-term effect of repeated TNFalpha administration 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. TNFalpha increased expression levels of the GluR1 subunit of AMPAR, but it 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. In in vivo animal studies, low doses of TNFalpha into the third ventricle of mouse brain enhanced anxiolytic behavior in the open field and elevated plus maze tests; however, high doses of TNFalpha showed a reduction. Taken together, the results suggest that TNFalpha-induced synaptogenesis occurred in an inverted U-shaped manner in cultured hippocampal neurons and had similar effects on animal models of anxiolytic behaviors. Our findings provide novel evidence that TNFalpha regulates synaptogenesis, which might play a crucial role in traumatic brain damage, inflammation, and psychiatric conditions.