Antidepressants and Intracellular Signaling Linked to BDNF

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）在抑郁症和抗抑郁样行为效应中发挥作用。在海马体中，BDNF表达减少，海马体是与抑郁症的病理生理学有关的脑区，通过暴露于压力，这是一些个体中与抑郁症有关的因素。相反，多种类型的抗抑郁药，以及电休克治疗（ECT），增加BDNF表达在海马在一个时间过程中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和“抑郁样”行为以及抗抑郁药物的行为反应之间的明确联系尚不清楚。该项目的主要目标是调查，1）BDNF的丢失是否会导致“抑郁样”行为和抗抑郁反应的变化，以及2）慢性抗抑郁治疗是否以BDNF依赖的方式对突触可塑性产生影响。一个主要目的是检查是否在3个互补遗传小鼠方法的海马中内源性BDNF的缺失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表现出减弱的行为反应。第二个目标将集中在BDNF在抗抑郁治疗后发挥下游效应中的作用。我们已经证明，在慢性抗抑郁药治疗后，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（NR 1）的磷酸化增加。以前的数据表明，BDNF可以调节NR 1磷酸化，从而增强NMDA受体功能。NMDA受体功能的变化可能介导突触可塑性的长期后果。我们将追踪慢性抗抑郁作用引起的NR 1磷酸化的增加，以检查这种上调是否通过BDNF的改变介导。总之，所提出的分子、细胞和行为研究有望促进我们对慢性抗抑郁药在海马中诱导的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.