Investigating the Role of the Astrocyte mGluR5 Pathway in Temporal Lobe Epilepsy

 描述(由申请人提供)：颞叶癫痫(TLE)是一种癫痫发作障碍，可能在某些脑损伤后数月至数年出现。一旦发病，TLE就很难治疗。目前NIH癫痫研究的基准包括更好地了解患者为什么会发生TLE。为此，癫痫研究人员必须了解大脑中非电细胞类型，如星形胶质细胞，在癫痫发展过程中的作用。星形胶质细胞具有直接改变神经元传递的能力。癫痫发作是一组神经元同步激活的结果。了解星形胶质细胞用来感知和操纵神经元活动的机制可能会发现抑制神经元活动和减少癫痫发作的新疗法。该项目的总体目标是更好地了解在多种TLE动物模型中星形胶质细胞上出现的受体的下游活性。这种受体被称为mGluR5，代表了星形胶质细胞感觉神经元活动的一种手段。作为对神经元活动的反应，mGluR5促进星形胶质细胞中钙活性的增加。然而，TLE中星形胶质细胞钙活性的潜在后果还不是很清楚。第一个目标将确定TLE发育的哪些阶段可能受到星形胶质细胞mGluR5活性的影响。成像mGluR5激活下游星形胶质细胞中的钙活性可以给出这一途径在TLE发育过程中何时发挥作用的指示。第二个目标将调查星形胶质细胞mGluR5活性的潜在后果。星形胶质细胞mGluR5活性的一个可能结果是星形胶质细胞对神经元突触进行了更紧密的物理包裹。更大的物理包裹的潜在影响包括星形胶质细胞一旦释放，隔离神经元谷氨酸的能力增强。实际上，这种高度的谷氨酸封存可能会降低兴奋性，代表大脑对损伤的自然反应。使用高分辨率电子显微镜技术可以观察到更大的物理包裹。一个重要的问题是，在受伤后，包裹的好处是否仍然存在。如果像包裹这样的反应机制在受伤后不能继续，这可能有助于解释为什么患者在受伤后几个月到几年会出现癫痫。

 DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is a seizure disorder that may arise months to years after certain brain injuries. Once developed, TLE is difficult to treat. A current NIH benchmark for epilepsy research includes a better understanding of why patients develop TLE. Towards that end, epilepsy researchers must understand the role of non-electrical cell types in the brain, like the astrocyte, in the epilepsy development process. Astrocytes have the ability to directly alter neuronal transmission. Seizures result from the synchronous activation of a population of neurons. Understanding the mechanisms that astrocytes utilize to sense and manipulate neuronal activity may uncover new therapies to dampen neuronal activity and reduce seizures. The overall goal of the project is to better understand the downstream activity of a receptor which emerges on the astrocyte in multiple animal models of TLE. This receptor, known as mGluR5, represents a means for the astrocyte to sense neuronal activity. In response to neuronal activity, mGluR5 promotes increased calcium activity in the astrocyte. However, the potential consequences of astrocyte calcium activity in TLE are not well understood. A first aim will determine which stages of TLE development could be impacted by astrocyte mGluR5 activity. Imaging the calcium activity in astrocytes downstream of mGluR5 activation can give an indication of when this pathway is functional during TLE development. A second aim will investigate a potential consequence of astrocyte mGluR5 activity. One suggested outcome of astrocyte mGluR5 activity is the closer physical enwrapping of neuronal synapses by the astrocyte. The potential impact of greater physical enwrapping includes a heightened ability of astrocytes to sequester neuronal glutamate, once released. In effect, this heighted glutamate sequestration could reduce excitability and represent a natural response of the brain to injury. Greater physical enwrapping can be observed with high-resolution electron microscopy techniques. An important question is whether the benefits of enwrapping persist after injury. If response mechanisms like enwrapping fail to continue after injury, it may help to explain why patients can develop epilepsy months to years after injury.