Role of neuronal nitric oxide in neuroplasticity-associated gene expression

描述（由申请人提供）：神经元型一氧化氮在神经可塑性相关基因表达中的作用哺乳动物脑的基本特征是其响应于神经活动的改变而经历持久修饰的能力。这种神经可塑性发生在早期发育到成年期，对正常的认知功能，包括学习和记忆至关重要。衰老和与衰老相关的大脑疾病，如阿尔茨海默病，其特征是认知能力丧失，这是一种与突触可塑性严重受损有关的现象。因此，了解突触可塑性的机制可能会提供新的方法来改善与正常和异常脑老化相关的认知功能障碍。NMDA型谷氨酸受体（NMDAR）在突触可塑性中起着重要作用，但调节其下游信号传导的因素和机制尚不完全清楚。由一氧化氮合酶（nNOS）的神经元亚型产生的一氧化氮（NO）已经成为NMDAR信号传导中的关键参与者。此外，NMDAR依赖的NO产生在各种形式的神经可塑性中起重要作用。然而，目前还不清楚这种短暂的分子如何导致神经可塑性的长期功能修饰。在该提议中提出的中心假设是，在NMDAR激活期间产生的NO在编码突触可塑性所需的关键蛋白质的基因的表达中起作用，所述关键蛋白质例如转录因子c-Fos和Egr-1以及突触效应蛋白BDNF和Arc。第一个目标将测试nNOS衍生的NO有助于神经可塑性相关基因表达的假设。第二个目的是检验nNOS衍生的NO对基因表达的影响是由ERK信号转导介导的这一假设。为了实现这些目标，我们将在小鼠须桶皮质和原代神经元培养中使用成熟的神经可塑性模型。将使用药理学抑制剂或nNOS缺陷小鼠研究NO的作用。 公共卫生相关性：老龄化和相关疾病（如阿尔茨海默病）中的认知功能障碍是一个主要问题，由于一般人群年龄的增加，其对公共卫生的影响迅速扩大。这些研究将增强我们对神经可塑性的细胞机制的理解，神经可塑性是突触的一种特性，对正常认知至关重要。从这些研究中获得的新信息可能为正常和异常衰老中认知丧失的新预防和治疗策略提供依据。

DESCRIPTION (provided by applicant): Role of neuronal nitric oxide in neuroplasticity-associated gene expression A fundamental feature of the mammalian brain is its ability to undergo long-lasting modifications in response to alterations in neural activity. This neuroplasticity occurs from early development into adulthood, and is essential for normal cognitive function, including learning and memory. Aging and aging-related brain disorders such as Alzheimer's disease are characterized by a loss of cognition, a phenomenon linked to a profound impairment of synaptic plasticity. Therefore, gaining an understanding of the mechanisms underlying synaptic plasticity may provide insight into new approaches to ameliorate the cognitive dysfunction associated with normal and abnormal brain aging. The NMDA-type glutamate receptor (NMDAR) plays a central role in synaptic plasticity, yet the factors and mechanisms which regulate its downstream signaling are not fully understood. Production of nitric oxide (NO) by the neuronal isoform of nitric oxide synthase (nNOS) has emerged as a key player in NMDAR signaling. In addition, NMDAR-dependent NO production plays an important role in various forms of neuroplasticity. However, it is unclear how this short-lived molecule results in the long-term functional modifications that characterize neuroplasticity. The central hypothesis set forth in this proposal is that NO produced during activation of NMDAR plays a role in the expression of genes encoding key proteins required for synaptic plasticity, such as the transcription factors c-Fos and Egr-1, and the synaptic effector proteins BDNF and Arc. The first aim will test the hypothesis that nNOS-derived NO contributes to neuroplasticity-associated gene expression. The second aim will test the hypothesis that the effects of nNOS-derived NO on gene expression are mediated by ERK signaling. To achieve these goals, we will use well-established models of neuroplasticity in the mouse whisker barrel cortex and in primary neuronal cultures. The role of NO will be studied using pharmacological inhibitors or nNOS-deficient mice. PUBLIC HEALTH RELEVANCE: Cognitive dysfunction in aging and related diseases, such as Alzheimer's disease, is a major problem with a rapidly expanding public health impact due to the increasing age of the general population. The proposed studies will enhance our understanding of the cellular mechanisms underlying neuroplasticity, a property of synapses that is essential for normal cognition. The new information derived from these studies may provide the bases for novel preventive and treatment strategies for cognitive loss in normal and abnormal aging.