Role of neuronal nitric oxide in neuroplasticity-associated gene expression

神经元一氧化氮在神经可塑性相关基因表达中的作用

• 批准号: 7774751
• 负责人: Eduardo Francisco Gallo
• 金额: $ 6.05万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774751
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Biochemical; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Calcium; Cell Nucleus; Chemosensitization; Code; Cognition; Communication; Development; Disease; Environment; Event; FOS gene; Gene Expression; General Population; Genes; Glutamate Receptor; Goals; Growth; Hippocampus (Brain); Impaired cognition; Impairment; In Vitro; Knockout Mice; Learning; Life; Link; Long-Term Potentiation; Mediating; Memory; Modeling; Modification; Mus; N-Methyl-D-Aspartate Receptors; Neuronal Plasticity; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pathway interactions; Play; Positioning Attribute; Postsynaptic Membrane; Preventive; Process; Production; Property; Protein Isoforms; Proteins; Public Health; Receptor Signaling; Role; Scaffolding Protein; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Synapses; Synaptic plasticity; Testing; Vibrissae; age related; aging brain; barrel cortex; base; cell type; cognitive function; experience; in vitro Model; in vivo; inhibitor/antagonist; insight; novel; novel strategies; postsynaptic; public health relevance; receptor function; relating to nervous system; research study; response; second messenger; transcription factor; treatment strategy

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.

描述（由申请人提供）：神经元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能够对神经活动的改变做出长期的改变。这种神经可塑性从早期发育到成年，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脑部疾病，如阿尔茨海默病，其特征是认知能力丧失，这一现象与突触可塑性的严重损害有关。因此，了解突触可塑性的机制可能为改善与正常和异常大脑衰老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重要作用，但调控其下游信号传导的因素和机制尚不完全清楚。一氧化氮合成酶（nNOS）的神经元异构体产生一氧化氮（NO）已成为NMDAR信号传导的关键参与者。此外，nmdar依赖性NO的产生在各种形式的神经可塑性中起着重要作用。然而，尚不清楚这种短寿命分子如何导致表征神经可塑性的长期功能改变。该提案提出的中心假设是，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。第一个目的将检验nnos衍生的NO有助于神经可塑性相关基因表达的假设。第二个目的将检验nnos衍生的NO对基因表达的影响是由ERK信号介导的假设。为了实现这些目标，我们将在小鼠须桶皮层和原代神经元培养中使用成熟的神经可塑性模型。我们将使用药物抑制剂或nnos缺陷小鼠来研究NO的作用。