BDNF Mutants: Genetic Models for Depressive Disorders

描述(申请人提供)：抑郁症是一种使人衰弱的疾病，影响数以百万计的个人，给社会带来巨大负担。仅在美国，每年就有近1000亿美元用于治疗重度和轻度抑郁症患者。然而，引发抑郁症的潜在分子机制仍有待阐明，以便为对当前形式的治疗无效的患者创造治疗替代方案。脑源性神经营养因子(BDNF)是设计新的治疗策略的潜在靶点。令人信服的证据表明，BDNF调节情感行为，但这种神经营养因子的具体作用和作用机制仍不清楚。我们最近使用cre重组酶/IoxP系统产生了BDNF的条件突变。这些小鼠出生前或出生后中枢神经系统中BDNF的耗竭不会像BDNF的全球耗尽那样影响它们的生存能力。这些突变体在行为上表现出戏剧性的变化，包括过度攻击性和对压力的高度敏感，这两者通常都是抑郁症的症状。我们建议使用这些突变体和我们目前正在产生的其他突变体作为抑郁障碍的遗传模型来剖析BDNF在行为调控中的作用。通过基因操作在与情绪障碍相关的大脑不同区域缺乏或过度表达BDNF的不同突变株，将使用抑郁症和攻击性的标准行为模型进行测试。

DESCRIPTION (provided by applicant): Depressive disorders are debilitating conditions that affect millions of individuals and create an enormous burden on society. Close to 100 billion dollars per year are spent treating patients with severe and mild forms of depression in the United States alone. However, the underlying molecular mechanisms that trigger depression remain to be elucidated so that treatment alternatives for patients that are unresponsive to the current forms of therapy can be created. A potential target for the design of novel treatment strategies is brain derived neurotrophic factor (BDNF). Compelling evidence shows that BDNF modulates affective behavior but the specific role and the mechanism of action of this neurotrophin remain elusive. We recently generated conditional mutations of BDNF using the cre recombinase/IoxP system. These mice have a pre or postnatal depletion of BDNF in the central nervous system that does not compromise their viability as the global depletion of BDNF does. These mutants display dramatic changes in behavior including hyperaggression and hypersensitivity to stress, both of which are often symptoms of depression. We propose using these mutants, and others that we are currently generating, as genetic models of depressive disorders to dissect the role of BDNF in the regulation of behavior. Different lines of mutants that through genetic manipulation have depletion or over expression of BDNF in different regions of the brain associated with mood disorders will be tested using standard behavioral models for depression and aggression.