CNS Development & Alcohol: Microglia-Neuron Interactions

描述（由申请人提供）：胎儿酒精综合征和相关疾病是已知的导致智力迟钝的主要原因。了解产前酒精暴露的神经病理学是至关重要的。由于对酒精破坏神经元发育的认识有限，目前缺乏预防胎儿酒精相关脑损伤的方法。为了解决这方面的知识差距，我们正在研究在发育过程中酒精介导的神经毒性中神经元-神经胶质相互作用的作用。小胶质细胞具有独特的重要性，因为它们提供神经元保护或通过病理激活介导神经元死亡。通过小脑颗粒细胞和小胶质细胞的共培养，我们发现小胶质细胞可以有效地保护神经元免受酒精毒性。我们对新生大鼠体内模型的研究表明，单次酒精剂量会导致发育中的小脑中近40%的小胶质细胞丢失，而存活的细胞似乎被病理激活。培养研究表明，酒精诱导的小胶质细胞损失是通过细胞凋亡发生的。因此，小胶质细胞的酒精消耗可能会破坏发育中的大脑中小胶质细胞衍生的神经保护。有趣的是，我们的研究还表明，酒精降低了pparγ蛋白的水平，此外，pparγ的药理激活可以降低酒精对小胶质细胞和神经元的细胞毒性。

DESCRIPTION (provided by applicant): Fetal alcohol syndrome and related disorders are the leading known cause of mental retardation. Understanding the neuropathology of prenatal alcohol exposure is critical. Methods for preventing alcohol associated brain damage in the fetus are lacking due to limited understanding of alcohol disruption of neuronal development. To address this gap in knowledge, we are investigating the role of neuronal-glial interactions in alcohol-mediated neurotoxicity during development. Microglia are uniquely important because they provide neuronal protection or, with pathologic activation, mediate neuronal death. Using co-cultures of cerebellar granule cells and microglia, we have found that microglia effectively protect neurons against alcohol toxicity. Our studies using an in vivo neonatal rat model reveal that a single alcohol dose produces almost 40% microglial loss in the developing cerebellum, and the surviving cells appear to be pathologically activated. Studies in culture suggest that alcohol-induced microglial loss is occurring by apoptosis. Thus, alcohol depletion of the microglial population may disrupt microglial-derived neuroprotection in the developing brain. Interestingly, our studies also reveal that alcohol reduces levels of the PPARgamma protein and, further, pharmacologic activation of PPARy can reduce alcohol cytotoxicity in microglia and neurons. To further these findings, we propose to investigate the overall hypothesis that alcohol disruption of microglial-neuronal interactions includes induction of microglial apoptosis, microglial activation, and suppression of microglial-derived neuroprotection. Complementary in vivo and in vitro models will be used to test this hypothesis. The specific aims of this proposal are to: 1. Determine whether alcohol-induced microglial cell loss in the developing cerebellum occurs by apoptosis. 2. Determine whether alcohol induces activation of the surviving microglial population. 3. Establish whether the deleterious effects of alcohol on developing microglia disrupt interactions between neurons and microglia. 4. Establish whether alcohol induced loss of neurons and microglia in the cerebellum involves suppression of PPARgamma, signaling and can be prevented by PPARgamma activation. Results of this study will provide better understanding of alcohol interference with the relationship between microglia and neurons. Application of this knowledge may provide new therapeutic strategies for intervention in the neuropathology caused by prenatal alcohol exposure.