Neuronal-Glial Interaction in the Treatment of Bipolar Disorder

促炎细胞因子，如肿瘤坏死因子-α(TNFpha)、白介素1(IL-1)和白介素6(IL-6)，最早是在免疫系统的细胞激活和细胞间通讯的背景下被发现的。早期关于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、头部创伤、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，免疫系统的过度激活与严重抑郁障碍的病理生理学有关。事实上，促炎细胞因子在大脑中表达，在那里它们已经被证明调节突触的可塑性。肿瘤坏死因子α由神经胶质细胞分泌，调节amino-3-hydroxyl-5-methyl-4-isoxazole-propionate的谷氨酸受体转运和神经可塑性。在本研究中，我们研究了肿瘤坏死因子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长期调节作用。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，用生物素化分析和免疫印迹法检测AMPA受体亚基表面表达的变化。用6 nM和60 nM的肿瘤坏死因子α处理海马神经元20分钟或1天后，AMPAR的GluR1亚单位的表达增加，但处理3天后无此作用。有趣的是，初步数据显示，在肿瘤坏死因子α处理20分钟后，GluR3表面的表达有增加的趋势。肿瘤坏死因子α作用20min、60min、1d和3d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-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。综上所述，这些发现提供了新的证据，表明胶质来源的TNFpha促进含有AMPA的突触的突触生成，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。

Pro-inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNFalpha), Interlukin-1 (IL-1) and Interlukin-6 (IL-6), were first discovered in the context of cellular activation and cell-to-cell communication 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, head 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 are expressed in the brain where they 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 by biotinylation assay and western blotting. Treatment of hippocampal neurons with TNFalpha (6 nM and 60 nM) for 20 min or 1 day increased expression of GluR1 subunit of AMPAR; however, no effect was observed after 3 days of treatment. Interestingly, preliminary data showed a trend of increase in GluR3 surface expression after 20 min of treatment with TNFalpha. TNFalpha applied for 20 min, 60 min, 1 day or 3 days 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.