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起作用。由于暴露在压力下，BDNF在海马中的表达减少，海马是与抑郁症的病理生理有关的大脑区域，这是与某些个体的抑郁症有关的因素。相反，多种类型的抗抑郁药以及电痉挛疗法（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，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BDNF与“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依赖的方式对突触可塑性产生影响。主要目的是研究在抑郁症动物模型中，三种互补遗传方法小鼠海马中内源性BDNF的缺失是否会产生“抑郁”表型。我们还将研究这些小鼠是否对抗抑郁药表现出减弱的行为反应。第二个目标将集中于BDNF在抗抑郁治疗后发挥下游作用的作用。我们已经证明，在慢性抗抑郁治疗后，谷氨酸受体亚基n -甲基- d -天冬氨酸1 （NR1）在蛋白激酶C （PKC）位点的磷酸化增加。先前的数据表明BDNF可能调节NR1的磷酸化，从而增强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影响。我们将通过慢性抗抑郁作用来研究NR1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，提出的分子、细胞和行为研究有望推进我们对慢性抗抑郁药在海马体中诱导的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.