| Budget Amount *help |
¥17,820,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2007: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2006: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Research Abstract |
Results of array studies have suggested abnormalities in expression of key oligodendrocyte and myelination genes in schizophrenia and bipolar disorder, however, protein levels in these disease brains have not yet been examined carefully. We investigated glia-associated protein expression in the grey matter of the prefrontal cortex (BA10) of schizophrenia and bipolar brains. We used samples from the Stanley brain collection, consisting of 10-15 schizophrenia, bipolar affective disorder, major depression and control brains. Western blot analysis was done to screen for differences in protein expression. We found a significant reduction of the key oligodendrocyte-related protein, NG2 chondroitm sulfate proteoglycan, in the grey matter of BA10 of schizophrenia and bipolar brains. Other glial markers such as glial fibrillary acidic protein, S100b (both for astrocyte), CNPase (For mature oligodendrocyte), and Ibal (for microglia) were unaltered. Instead, we found significant increase in the l
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evels of neuron specific enolase, a marker for neurons, in the major depression brains when compared to control brains, supporting partially some previous findings that neuron numbers in the major depression brains increased when compared to those in control brains. Since NG2 is a marker for immature but not mature oligodendrocyte, these data suggest that development of oligodendrocytes or dysfunction of oligodendrocyte progenitor cells may play important roles in the pathogenesis of schizophrenia and bipolar disorder.
Several thousand new neurons are produced each day in the adult mammalian hippocampus. Recent evidence have revealed that about 10-20% of newly generated neurons in the dentate gyrus are GABAergic (Liu et al., J Neurosci, 23;732, 2003) and may partly be derived from NG2 proteoglycan-expressing hippocampal progenitor cells (NG2-HPCs)(Belachew et al., JCB, 161;169, 2003). We have recently established a novel method to isolate and expand NG2-HPCs from adult rat hippocampus with about 90% purity in serum-free medium (see details in the poster by Yu et al. 517.7/B39 in this meeting). We investigated the potential of cultured NG2-HPCs for the GABAergic neuronal differentiation. NG2-HPCs already contain certain amount of GABA in their cell bodies and processes since anti-GABA antibodies stained these structures and the preabsorption of the antibodies with GABA-conjugated BSA completely abolished the stainings. Glutamic acid decarboxylase (GAD) inhibitors reduced these GABA immunostainings, suggesting that at least part of GABA may be synthesized by NG2-HPCs. Single treatment with brain derived neurotrophic factor (BDNF) or platelet derived growth factor AA(PDGF-AA) for 7 days did not affect the GABA contents in NG2-HPCs significantly, however BDNF increased MAP2a/b while PDGF-AA decreased NG2 expression. Interestingly, combined treatment with BDNF and PDGF-AA for 7 days increased the GABA contents in NG2-HPCs in association with the increased MAP22a/b, GAD67, and vesicular GABA transporter expression, with the decreased NG2 expression and with the neuron-like morphological changes. These effects of BDNF and PDGF-AA were most obvious in cells located in the periphery of the colonies, suggesting that cell-cell contact may also play important roles in the neuronal differentiation of these cells. In contrast, BDNF and PDGF-AA failed to increase Toj-1 and parvalbumin immunoreactivities in NG2-HPCs, suggesting that other factors axe also required to achieve complete neuronal differentiation. Taken together, our data is highly suggestive that combined treatment with BDNF and PDGF-AA promote some aspects of the GABAergic neuronal differentiation of adult NG2-HPCs in vitro. Less
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