Neuronal-Glial Interaction in the Treatment of Bipolar D

现在有令人信服的证据表明，放射状胶质细胞不仅具有引导新生神经元的潜力，而且还具有自我更新和生成神经元和星形胶质细胞的潜力。最近的数据还表明，星形胶质细胞使中枢神经系统神经元上成熟的、有功能的突触数量增加了7倍，表明神经胶质细胞可以深刻地调节中枢神经系统突触的数量。神经胶质细胞还在调节突触谷氨酸水平、中枢神经系统能量平衡、营养因子释放等方面发挥重要作用，并与神经元形成动态、复杂的突触网络。然而，由于神经成像、死后形态测量和微阵列研究的融合，神经胶质功能障碍在主要精神疾病中的可能性直到最近才得到认真考虑，这些研究清楚地揭示了精神分裂症和情绪障碍中神经胶质细胞的异常。为了研究LI对神经胶质细胞和神经元生长的影响，我们建立了星形胶质细胞和神经元原代培养体系。 分别用或不加Li处理细胞。我们发现，锂促进了星形胶质细胞的增殖，它可能间接地(通过释放胶质细胞中的因子)调节神经元的分化。星形胶质细胞可诱导多能未成熟神经元表达星形胶质细胞表型。接下来，我们将研究细胞信号在星形胶质细胞增殖和神经元分化过程中的变化，以研究Li诱导作用的可能分子机制。此外，我们还将检测Li是否影响CNS中另一种胶质细胞和星形胶质细胞前体--少突胶质细胞的生长。为了更明确地研究这一点，我们进行了一系列体外和体内研究，检测锂对少突胶质细胞的影响。慢性锂处理能显著增加少突胶质细胞总数，且呈剂量依赖关系，1.0 mM锂处理效果最好。为了确定锂是否影响BrdU的掺入，用BrdU处理少突胶质细胞6h，不加或不加锂(1.0 mM)。免疫细胞化学法检测BrdU掺入。锂离子处理后，BrdU标记细胞明显增多。为了进一步确定这些BrdU标记细胞的细胞表型，用免疫细胞化学方法检测O4的表达。BrdU阳性细胞也为O4+。在数量上，锂处理组BrdU阳性少突胶质细胞的百分比以及BrdU+O4+细胞的百分比显著增加。我们的数据首次表明，慢性锂对少突胶质细胞有重要影响。这些观察结果提出了一种可能性，即锂可能有助于纠正白质束中的异常，从而恢复调节情感、认知和运动症状的关键回路的功能。我们的数据表明，Li促进了少突胶质细胞的增殖。这些机制可能为改善严重神经精神障碍的长期治疗提供一个潜在的靶点。

There is now compelling evidence that radial glial cells have the potential, not only to guide newly born neurons, but also to self-renew and to generate both neurons and astrocytes. Recent data has also shown that astrocytes increase the number of mature, functional synapses on CNS neurons by sevenfold, demonstrating that CNS synapse number can be profoundly regulated by glia. Glial cells are also known to play critical roles in regulating synaptic glutamate levels, CNS energy eostasis, liberation of trophic factors, and indeed form dynamic, complex synaptic networks with neurons. Nevertheless, the possibility of glial dysfunction in major psychiatric disorders has only recently received serious consideration due to the converging neuroimaging, postmortem morphometric and microarray studies, which have clearly revealed glial abnormalities in schizophrenia and mood disorders. To examine the effect of Li on glia and neuron growth, we have established astrocyte and neuronal primary culture system. Cells were treated with or without Li. We found that the astrocyte, whose proliferation is increased by lithium, may indirectly (via liberation of factors from glial cells) regulate neuronal differentiation. Astrocytes may induce the pluripotent immature neuron to express an astrocytic phenotype. Next, we will examine the alteration of cell signaling in astrocyte proliferation and neuronal differentiation to study the possible Molecular mechanism of Li-induced action In addition, we will examine whether Li affects growth of oligodendricyte, another glia and precursor of astrocytes in CNS. To investigate this more definitively, we have undertaken a series of in vitro and in vivo studies examining lithium's effects on oligodendrocytes. Chronic lithium treatment significantly increased the total number of oligodendrocytes in a dose-dependent manner, with a maximal effect was observed with 1.0 mM lithium. To determine whether lithium affects BrdU incorporation, oligodendrocytes were treated with BrdU for 6 h in the absence or presence of lithium (1.0 mM). BrdU incorporation was determined by immunocytochemistry. BrdU-labeled cells were markedly increased by lithium treatment. To further determine the cell phenotype of these BrdU-labeled cells, O4 expression was examined by immunocytochemistry. BrdU-positive cells were also O4+. Quantitatively, the percentage of BrdU-positive oligodendrocyte, as well as that of BrdU+O4+ cells were significantly increased by the lithium treatment. Our data demonstrate -- for the first time - that chronic lithium exerts a major effect on oligodendrocytes. These observations raise the possibility that lithium may serve to correct abnormalities in white matter tracts, thereby restoring the functioning of critical circuits mediating affective, cognitive and motoric symptoms. Our data have demonstrated that Li increased oligodendicytes proliferation. These mechanisms may provide a potential target for improved long-term therapeutics for severe neuropsychiatric disorders.