The Role of Glutamate and Glutamate Receptors in Mouse Models for Emotional Behaviors and Mood Disorders

近年来的研究表明，神经递质谷氨酸参与了情绪障碍的病理生理和治疗。这项提议的目的是为了更好地理解谷氨酸在情感障碍小鼠模型中的作用。我们想要找出谷氨酸水平（再摄取受损）在多大程度上是重要的，以及谷氨酸诱导的信号传导的具体改变如何分别成为与压力相关的“疾病状态”或抗逆性的基础。我们将不同的谷氨酸稳态和谷氨酸信号受损的转基因小鼠进行行为学、神经内分泌学、分子和药理学研究。将分析多种谷氨酸摄取（EAAT-1和EAAT-2转运体）或谷氨酸能神经传递特异性缺陷的突变小鼠，例如嗜离子性（AMPA-和nmda型）谷氨酸受体（GluR-A, GluR-C, NR-1, NR-2A）。所有小鼠都将接受应激性抑郁模型（习得性无助，慢性压力）和情绪行为测试。我们将使用一步一步的方法来测试情绪障碍的“谷氨酸假说”，从传统的突变菌株开始，证明基因缺失（谷氨酸受体/转运基因）对情绪行为的最大影响。这将识别那些有助于行为表型的基因。然后，我们将通过将基因缺失限制在特定的大脑区域来确定感兴趣的基因相关的大脑区域（例如海马体，前脑）。作为概念的证明，我们将尝试通过转基因或病毒介导的基因转移来拯救特定的行为表型。我们将研究在小鼠抑郁模型中塑造情绪行为的谷氨酸能药物是否改变了谷氨酸受体基因缺失的小鼠的效果。我们将试图确定分子/生化/细胞信号通路的改变，这些信号通路已被假定为抑郁症的发病机制或病理生理学。总之，这些实验将提高我们对情绪障碍病理生理学基础的神经生物学过程的认识，并可能为抗抑郁治疗指明新的靶点。

Recent studies have indicated that the neurotransmitters glutamate is involved in the pathophysiology and treatment of mood disorders. The goal of this proposal is to better understand the role of glutamate in mouse models for affective disorders. We would like to find out to which extent just levels of glutamate (impaired reuptake) are important and how specific alterations of glutamate induced signalling underlies stress-related "disease states" or stress-resistance, respectively. We subject different genetically modified mice with impaired glutamate homeostasis and glutamate signalling to behavioral, neuroendocrinological, molecular and pharmacological studies. A variety of mutant mice with specific deficits in glutmate uptake (EAAT-1 and EAAT-2 transporters) or glutamatergic neurotransmission, e.g. of ionotropic (AMPA- and NMDA-type) glutamate receptors (GluR-A, GluR-C, NR-1, NR-2A) will be analysed. All mice will be subjected to stressinduced depression models (learned helplessness, chronic stress) and a testing battery for emotional behaviors. We will use a step by step approach to test the "glutamate hypothesis" of mood disorders, starting with conventional mutant strains demonstrating the maximum effect of gene deletions (glutamate receptors/transporters genes) on emotional behavior. This will identity those genes that contribute to a behavioral phenotype. We will then identify the brain regions (e.g. hippocampus, forebrain) where the genes of interest are relevant by restricting the gene deletions to specific brain areas. As a proof of concept we will try to rescue specific behavioral phenotypes by a transgenic or alternatively a virus-mediated gene transfer. We will investigate whether glutamatergic drugs that shape emotional behavior in murine depression models have altered effects in mice with genetically depleted glutamate receptors. We will try to identify alterations in molecular/biochemical/cellular signalling pathways that have been postulated for the pathogenesis or pathophysiology of depression. Altogether, these experiments will improve our knowledge of the neurobiologal processes underlying the pathophysiology of mood disorders, and may indicate novel targets for antidepressant therapy.