Mechanisms of Reelin Signaling in the Adult Hippocampus

描述（由申请人提供）：载脂蛋白E（ApoE）和阿尔茨海默病之间存在功能性联系。ApoE使其携带者易患这种疾病的潜在生化机制尚不清楚，目前仍在争论中。一种模型表明，在神经元表面大量表达的ApoE受体家族的成员，特别是ApoE 2和VLDL受体，可能参与了这一病理过程。其中两种ApoE受体，VLDL受体和ApoER 2，也是Reelin的受体，Reelin是一种在大脑发育过程中调节神经元迁移的信号蛋白。成人Reelin的GABA能中间神经元的表达与海马中ApoE 2和VLDL受体的高表达相结合，强烈表明这些系统在成人CNS中的作用。这一建议的基础是这样一个假设，即在成年CNS中，Reelin/ApoE 2/VLDL受体系统作为神经传递的调节剂具有功能。为了更好地了解这种受体系统在哺乳动物海马功能中的作用，我们将进行四个具体目标： 目的1：确定ApoE 2和VLDL受体缺陷小鼠是否表现出学习记忆和海马突触功能的缺陷。 目的2：确定Reelin应用和Reelin信号中断对成年海马突触传递和可塑性的影响。 目的3：验证Reelin通过Src酪氨酸激酶以ApoER 2/VLDL受体依赖性方式磷酸化NMDA受体的假设。 目的4：确定ApoER 2胞质结构域的结构/功能关系。 这些研究将为脂蛋白受体ApoE 2和VLDL在哺乳动物学习和记忆机制以及海马突触传递和可塑性中的作用提供基本的理解。此外，这些研究将提供第一次深入了解通过这些受体的Reelin信号转导调节海马功能的机制。总的来说，这项工作将有助于阐明这些ApoE受体在神经退行性疾病（如阿尔茨海默病）中的潜在作用。

DESCRIPTION (provided by applicant): There is a functional connection between Apolipoprotein E (ApoE) and Alzheimer's disease. The underlying biochemical mechanism by which ApoE predisposes its carriers to this disease is not known and is under debate. One model suggests that members of a family of ApoE receptors that are abundantly expressed on the surface of neurons, specifically the ApoE2 and VLDL receptors, may be involved in this pathological process. Two of these ApoE receptors, the VLDL receptor and the ApoER2, are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. Adult expression of Reelin by GABA-ergic interneurons coupled to a high expression of ApoE2 and VLDL receptors in the hippocampus strongly suggests a role for these systems in adult CNS. The basis for this proposal is the hypothesis that there is a function of the Reelin/ApoE2/VLDL receptor system as a modulator of neurotransmission in the adult CNS. To better understand the role of this receptor system in mammalian hippocampal function, we will undertake four specific aims: Aim 1: Determine if mice deficient for ApoE2 and VLDL receptors exhibit deficits in learning and memory and hippocampal synoptic function. Aim 2: Determine the effect of Reelin application and Reelin signaling disruption on adult hippocampal synaptic transmission and plasticity. Aim 3: Test the hypothesis that Reelin acts through Src tyrosine kinase to phosphorylate NMDA receptors in an ApoER2/VLDL receptor-dependent manner. Aim 4: Determine the structure/function relationship for ApoER2 cytoplasmic domains. These studies will provide a basic understanding of the role for the lipoprotein receptors ApoE2 and VLDL in mammalian learning and memory mechanisms and hippocampal synaptic transmission and plasticity. Moreover, these studies will provide the first insight into the mechanisms of Reelin signaling through these receptors to modulate hippocampal function. Overall, this work will help shed light on the potential role of these ApoE receptors in neurodegenerative disorders, such as Alzheimer's disease.