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.
| Schloesser, Robert J; Manji, Husseini K; Martinowich, Keri (2009) Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response. Neuroreport 20:553-7 |
