Antidepressants and Intracellular Signaling Linked to BDNF

抗抑郁药和与 BDNF 相关的细胞内信号传导

• 批准号: 6975767
• 负责人: LISA M MONTEGGIA
• 金额: $ 24.96万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6975767
• 关键词: NMDA receptors; antidepressants; behavioral /social science research tag; behavioral medicine; biological signal transduction; brain derived neurotrophic factor; depression; excitatory aminoacid; gene targeting; genetically modified animals; hippocampus; laboratory mouse; mental disorder chemotherapy; mood disorders; neural plasticity; phenotype; phosphorylation; synapses; transfection

DESCRIPTION (provided by applicant): Recent studies have suggested that brain-derived neurotrophic factor (BDNF) plays a role in depression and antidepressant-like behavioral effects. BDNF expression is decreased in the hippocampus, a brain region implicated in the pathophysiology of depression, by exposure to stress, a factor implicated in depression in some individuals. Conversely, multiple classes of antidepressants, as well as electrocpnvulsive therapy (ECT), increase BDNF expression in the hippocampus in a time course consistent with the therapeutic action of these drugs. BDNF, the most prevalent growth factor in the brain, can then exert alterations in neuronal plasticity through specific signaling pathways. However, a clear link between the role of endogenous BDNF and 'depression-like' behavior and in the behavioral responses to antidepressant drugs remains unclear. The main goal of this project is to investigate, 1) whether the loss of BDNF produces changes in 'depressive-like' behavior and antidepressant responses and, 2) whether chronic antidepressant treatment exerts effects on synaptic plasticity in a BDNF dependent manner. 1 major aim is to examine whether the loss of endogenous BDNF in the hippocampus of 3 complementary genetic mouse approaches produces a 'depressive' phenotype in animal models of depression. We also will examine whether these mice display attenuated behavioral responses to antidepressants. A second aim will focus on the role of BDNF in exerting downstream effects following antidepressant treatment. We have demonstrated an increase in the phosphorylation of the glutamate receptor subunit, N-methyl-D-aspartate 1 (NR1) on a protein kinase C (PKC) site following chronic antidepressant treatment. Previous data has shown that BDNF may regulate NR1 phosphorylation, which then potentiates NMDA receptor function. Changes in NMDA receptor function could mediate long-term consequences in synaptic plasticity. We will pursue the increase in NR1 phosphorylation by chronic antidepressant action to examine whether this upregulation is mediated via alterations in BDNF. Together, the proposed molecular, cellular, and behavioral studies promise to advance our understanding of the role of BDNF that chronic antidepressants induce in the hippocampus.

描述（由申请人提供）：最近的研究表明，脑源性神经营养因子（BDNF）在抑郁和抗抑郁样行为效应中发挥作用。海马体（与抑郁症病理生理学有关的大脑区域）中的 BDNF 表达会因暴露于压力而减少，压力是某些个体抑郁症的一个因素。相反，多种抗抑郁药以及电刺激疗法 (ECT) 会增加海马中 BDNF 的表达，其时间过程与这些药物的治疗作用一致。 BDNF 是大脑中最普遍的生长因子，可以通过特定的信号通路改变神经元的可塑性。然而，内源性 BDNF 的作用与“抑郁样”行为以及对抗抑郁药物的行为反应之间的明确联系仍不清楚。该项目的主要目标是调查：1）BDNF 的丧失是否会产生“抑郁样”行为和抗抑郁反应的变化，2）长期抗抑郁治疗是否以 BDNF 依赖性方式对突触可塑性产生影响。 1 个主要目的是检查 3 种互补基因小鼠方法的海马内源性 BDNF 的缺失是否会在抑郁动物模型中产生“抑郁”表型。我们还将检查这些小鼠是否表现出对抗抑郁药物减弱的行为反应。第二个目标将集中于 BDNF 在抗抑郁治疗后发挥下游效应的作用。我们已经证明，长期抗抑郁治疗后，蛋白激酶 C (PKC) 位点上的谷氨酸受体亚基 N-甲基-D-天冬氨酸 1 (NR1) 磷酸化有所增加。先前的数据表明 BDNF 可以调节 NR1 磷酸化，从而增强 NMDA 受体功能。 NMDA 受体功能的变化可能会介导突触可塑性的长期后果。我们将通过长期抗抑郁作用来追踪 NR1 磷酸化的增加，以检查这种上调是否是通过 BDNF 的改变介导的。总之，所提出的分子、细胞和行为研究有望增进我们对长期抗抑郁药物在海马体中诱导的 BDNF 作用的理解。