Seizures Epileptogenesis and TrkB Transactivation

描述（由申请人提供）：神经营养因子受体TrkB在神经元存活和分化以及突触结构、功能和可塑性中起关键作用。TrkB信号传导也与多种精神和神经疾病有关。值得注意的是，TrkB在边缘癫痫发生期间被激活，并且是边缘癫痫发生所需的。了解TrkB被激活的机制将有助于了解其在健康和疾病中的多效性功能。反式激活是指给定受体及其下游信号传导被不与受体直接相互作用的刺激激活的过程，这是一种不同于神经营养因子如BDNF激活TrkB的机制。我们最近发现，二价阳离子，锌，可以反式激活TrkB在培养的神经元的活动依赖性和神经营养因子的独立机制。锌是否在体内反式激活TrkB，如果是这样，它的生理和病理后果是未知的。该应用集中在锌对TrkB的假设反式激活上，无论是在体内还是在离体切片中。将评估三个水平的分析：离体膜和组织中pTrkB和TrkB的生物化学和免疫组织化学测量;离体切片中海马苔藓纤维-CA 3锥体突触的增强;以及体内点燃和匹罗卡品模型中的癫痫发生。我们将确定是否泡状锌transactivates TrkB在体内，是否泡状锌是所需的苔藓纤维CA 3锥体突触的LTP，以及是否泡状锌是所需的边缘癫痫在体内。所提出的工作的成功完成将阐明锌在体内TrkB反式激活中的作用，从而阐明神经营养因子和非神经营养因子配体对TrkB的激活。了解TrkB是如何被激活的是很重要的，因为TrkB信号在哺乳动物神经系统中的发育和成年以及健康和疾病中的重要作用。 公共卫生相关性：神经营养因子受体TrkB在哺乳动物神经系统的健康和疾病功能中起关键作用。了解TrkB被激活的机制将有助于深入了解其在健康和疾病中的许多功能。在这里，我们将测试激活TrkB的新的和意想不到的机制是否发生在活小鼠中。也就是说，我们询问二价阳离子锌是否在体内激活TrkB。

DESCRIPTION (provided by applicant): The neurotrophin receptor, TrkB, serves a pivotal role in neuronal survival and differentiation as well as in synaptic structure, function, and plasticity. TrkB signaling has also been implicated in diverse psychiatric and neurological disorders. Notably, TrkB is activated during and is required for limbic epileptogenesis. Understanding the mechanisms by which TrkB is activated will provide insight into its pleiotropic functions in health and disease. Transactivation refers to the process whereby a given receptor and its downstream signaling is activated by a stimulus that does not interact directly with the receptor, a mechanism distinct from activation of TrkB by neurotrophins such as BDNF. We recently discovered that the divalent cation, zinc, can transactivate TrkB in cultured neurons by an activity dependent and neurotrophin independent mechanism. Whether zinc transactivates TrkB in vivo and, if so, it's physiological and pathological consequences are unknown. This application centers on the hypothesized transactivation of TrkB by zinc, both in vivo and in slices ex vivo. Three levels of analysis will be assessed: biochemical and immunohistochemical measures of pTrkB and TrkB in membranes and tissue ex vivo; potentiation of the hippocampal mossy fiber-CA3 pyramid synapse in slices ex vivo; and epileptogenesis in the kindling and pilocarpine models in vivo. We will determine whether vesicular zinc transactivates TrkB in vivo; whether vesicular zinc is required for LTP of the mossy fiber-CA3 pyramid synapse; and whether vesicular zinc is required for limbic epileptogenesis in vivo. Successful completion of the proposed work will clarify the role of zinc in transactivation of TrkB in vivo and thereby shed light on the activation of TrkB by both neurotrophin and non-neurotrophin ligands. Understanding how TrkB is activated is important because of the seminal role of TrkB signaling in the mammalian nervous system in development and adulthood and in both health and disease. PUBLIC HEALTH RELEVANCE: The neurotrophin receptor, TrkB, serves a pivotal role in the function of the mammalian nervous system in both health and disease. Understanding the mechanisms by which TrkB is activated will provide insight into its many functions in health and disease. Here we will test whether a novel and an unexpected mechanism of activating TrkB, occurs in living mice. That is, we ask whether the divalent cation zinc activates TrkB in vivo.