Antidepressants and Intracellular Signaling Linked to BDNF

描述(申请人提供)：最近的研究表明，脑源性神经营养因子(BDNF)在抑郁症和抗抑郁药样行为效应中发挥作用。脑源性神经营养因子在海马区的表达减少，海马区是与抑郁症的病理生理学有关的大脑区域，暴露在压力中，这是一些人患抑郁症的一个因素。相反，多类抗抑郁药物以及电刺激疗法(ECT)在与这些药物的治疗作用相一致的时间过程中增加了海马区BDNF的表达。脑源性神经营养因子是大脑中最普遍的生长因子，它可以通过特定的信号通路改变神经元的可塑性。然而，内源性脑源性神经营养因子与类似抑郁的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。本项目的主要目的是研究：1)BDNF的缺失是否会导致“抑郁样”行为和抗抑郁反应的改变；2)慢性抗抑郁治疗是否以BDNF依赖的方式影响突触的可塑性。1主要目的是检验3种互补遗传方式的小鼠海马区内源性脑源性神经营养因子的缺失是否会在抑郁症动物模型中产生“抑郁”表型。我们还将检查这些小鼠是否对抗抑郁药物表现出减弱的行为反应。第二个目标将集中在BDNF在抗抑郁药物治疗后发挥下游效应方面的作用。我们已经证明，在慢性抗抑郁药物治疗后，蛋白激酶C(PKC)位点上谷氨酸受体亚单位N-甲基-D-天冬氨酸1(NR1)的磷酸化增加。以往的数据表明，BDNF可能调节NR1的磷酸化，进而增强NMDA受体的功能。NMDA受体功能的改变可能介导突触可塑性的长期后果。我们将通过慢性抗抑郁作用来增加NR1的磷酸化，以检查这种上调是否通过BDNF的改变来调节。总之，拟议的分子、细胞和行为研究有望促进我们对慢性抗抑郁药物在海马区诱导的BDNF作用的理解。

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.