Dysregulation of glial glutamate transmission as a model of depressive illness

描述（由申请人提供）：重度抑郁症（MDD）与皮层异常有关，包括神经胶质细胞减少（例如Ongur等人，1998年）、谷氨酸能神经传递失调（Paul和Skolnick 2003年）和神经元活动升高（Mayberg等人，2005年）。因为神经胶质细胞在运输兴奋性神经递质谷氨酸中起着关键作用，这些病理很可能是相关的。最近的报告通过证明氯胺酮（NMDA（谷氨酸）受体的拮抗剂）在人类和实验动物中具有抗抑郁作用，表明谷氨酸能功能与抑郁症治疗之间存在因果关系（Maeng et al. 2007; Zarate et al. 2006）。此外，最近的研究表明，神经胶质消融可以在动物身上产生类似抑郁的效果（Banasr et al. 2008）。因此，越来越多的证据表明，谷氨酸能传递和神经胶质细胞功能可能在情绪障碍的病理生理和缓解中发挥重要作用。基于这些观察，我假设神经胶质谷氨酸运输减少可以诱发抑郁症的迹象。我将通过防止神经胶质细胞运输谷氨酸的药理学操作和两种互补的行为测试来验证这一假设，这两种行为测试是指动机，颅内自我刺激和位置条件反射。虽然重度抑郁症是由一些复杂的症状组成的，比如毫无价值的感觉和自杀的想法，但抑郁症的一些症状可以通过这些行为测试来模拟，包括对快乐的兴趣降低（快感缺乏）和抑郁情绪（烦躁不安）。使用这些工具和显微注射技术，我将确定情绪是由整个大脑的神经胶质谷氨酸传导调节的，还是局限于前额皮质（PFC）。这些研究提供了一种存在于抑郁症患者身上的异常动物模型，并试图确定它们是否与抑郁症的病因有关。这是一种新颖的方法，它将扩大我们对啮齿动物情绪调节中与人类抑郁症相关的缺陷的病理生理学相关性的理解，这很有可能促进新的更有效治疗策略的发展。

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is associated with cortical abnormalities, including fewer glial cells (e.g. Ongur et al. 1998), dysregulated glutamatergic neurotransmission (Paul and Skolnick 2003), and elevated neuronal activity (Mayberg et al. 2005). Because glial cells play a key role in trafficking the excitatory neurotransmitter glutamate, it is likely that these pathologies are related. Recent reports suggest a causal link between glutamatergic function and the treatment of depression by demonstrating that ketamine, an antagonist at NMDA (glutamate) receptors, has antidepressant effects in humans and laboratory animals (Maeng et al. 2007; Zarate et al. 2006). In addition, very recent work suggests that glial ablation can produce depressive-like effects in animals (Banasr et al. 2008). Thus there is mounting evidence that glutamatergic transmission and glial cell function may play important roles in both the pathophysiology and relief of mood disorders. Based on these observations, I hypothesize that reduced glial glutamate trafficking can induce signs of depression. I will test this hypothesis using pharmacological manipulations that prevent glutamate trafficking by glial cells and two complimentary behavioral tests that index motivation, intracranial self-stimulation and place conditioning. Although MDD is made up of complex symptoms such as feelings of worthlessness and suicidal ideation, some aspects of the symptoms of depression can be modeled using these behavioral tests including diminished interest in pleasure (anhedonia) and depressed mood (dysphoria). Using these tools and microinjection techniques, I will determine if mood is regulated by glial glutamate transmission throughout the brain or restricted to the prefrontal cortex (PFC). These studies provide an animal model of abnormalities that are present in depressed humans and seek to determine whether they contribute to the etiology of depression. This is a novel approach that will broaden our understanding of the pathophysiological relevance of deficits that are associated with depression in humans in the regulation of mood in rodents, which has a high likelihood of facilitating the development of new more effective treatment strategies. PUBLIC HEALTH RELEVANCE: The proposed studies seek to enhance our understanding of the causes of major depression. This will be accomplished by exploring the relevance of glial cell deficits that are associated with depression in humans in the regulation of mood in rodents. This work has a high likelihood of facilitating the development of new more effective treatment strategies.