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，星形胶质细胞增加了7倍的CNS神经元上的成熟的功能性突触的数量，表明CNS突触的数量可以被神经胶质细胞深刻地调节。还已知神经胶质细胞在调节突触谷氨酸水平、CNS能量平衡、营养因子释放中起关键作用，并且确实与神经元形成动态的复杂突触网络。然而，神经胶质功能障碍的可能性，主要精神疾病最近才得到认真考虑，由于收敛的神经影像学，死后形态和微阵列研究，这清楚地揭示了神经胶质异常的精神分裂症和情绪障碍。为了研究锂对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的原代培养系统。 用或不用Li处理细胞。我们发现，星形胶质细胞，其增殖增加的锂，可能间接（通过释放因子从神经胶质细胞）调节神经元分化。星形胶质细胞可以诱导多能未成熟神经元表达星形胶质细胞表型。接下来，我们将研究星形胶质细胞增殖和神经元分化中细胞信号的改变，以研究Li诱导作用的可能分子机制。此外，我们将研究Li是否影响CNS中另一种胶质细胞和星形胶质细胞前体寡树突细胞的生长。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，检查锂对少突胶质细胞的影响。慢性锂处理以剂量依赖性方式显著增加了少突胶质细胞的总数，在1.0 mM锂时观察到最大效应。为了确定锂是否影响BrdU掺入，少突胶质细胞用BrdU在锂（1.0 mM）存在或不存在下处理6小时。免疫细胞化学法测定BrdU掺入。BrdU标记的细胞显着增加锂处理。为了进一步确定这些BrdU标记细胞的细胞表型，通过免疫细胞化学检查O4表达。BrdU阳性细胞也呈O4+。锂处理后，BrdU阳性的少突胶质细胞和BrdU+O4+细胞的数量、百分比均显著增加。我们的数据首次表明，长期锂对少突胶质细胞产生重大影响。这些观察结果提高了锂可能有助于纠正白色物质束异常的可能性，从而恢复介导情感、认知和运动症状的关键回路的功能。我们的数据表明，锂增加寡树突细胞增殖。这些机制可能为改善严重神经精神疾病的长期治疗提供了潜在的靶点。

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.