Role of neuronal nitric oxide in neuroplasticity-associated gene expression

描述(申请人提供)：神经一氧化氮在神经可塑性相关基因表达中的作用哺乳动物大脑的一个基本特征是它有能力对神经活动的变化做出长期的修改。这种神经可塑性从早期发育到成年，对包括学习和记忆在内的正常认知功能是必不可少的。衰老和阿尔茨海默病等与衰老相关的大脑疾病的特征是认知丧失，这一现象与突触可塑性的严重损害有关。因此，了解突触可塑性的潜在机制可能为改善与正常和异常脑老化相关的认知功能障碍提供新的途径。NMDA型谷氨酸受体(NMDAR)在突触可塑性中起着核心作用，但调节其下游信号的因素和机制尚不完全清楚。由神经元亚型一氧化氮合酶(NNOS)产生的一氧化氮(NO)在NMDAR信号转导中起着关键作用。此外，依赖NMDAR的NO的产生在各种形式的神经可塑性中发挥着重要作用。然而，目前还不清楚这种短暂的分子是如何导致神经可塑性的长期功能修饰的。这一建议提出的中心假设是，在NMDAR激活过程中产生的NO在编码突触可塑性所需关键蛋白的基因表达中发挥作用，如转录因子c-Fos和Egr-1，以及突触效应蛋白BDNF和Arc。第一个目标将检验nNOS来源的NO有助于神经可塑性相关基因表达的假设。第二个目的将检验nNOS来源的NO对基因表达的影响是通过ERK信号转导的假设。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。将使用药物抑制剂或nNOS缺陷小鼠来研究NO的作用。 公共卫生相关性：老年性认知障碍和相关疾病，如阿尔茨海默病，是一个主要问题，由于普通人口年龄的增加，对公共健康的影响迅速扩大。拟议中的研究将加强我们对神经可塑性背后的细胞机制的理解，神经可塑性是突触的一种属性，对正常认知至关重要。来自这些研究的新信息可能为新的预防和治疗正常衰老和异常衰老中的认知损失的策略提供基础。

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.