The role of Homer1a-mediated regulation of glutamatergic signalling in the antidepressant therapy

Homer1a 介导的谷氨酸信号调节在抗抑郁治疗中的作用

• 批准号: 326237897
• 负责人: Professor Dr. Claus Normann, since 11/2021
• 金额: --
• 依托单位: Klinik für Neurochirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/326237897?language=en
• 关键词: role; Homer1a; mediated; regulation; glutamatergic

Major depressive disorder is the most common mental diseases. The widely used monoamine-based antidepressant drugs require weeks to month to improve symptoms, have low response rates and often cause side effects. Therefore, the search for mechanistically novel and more effective therapeutic options for depression is currently a research priority.We have identified that the synaptic plasticity protein Homer1a is an important element for the antidepressant therapy. The modulation of glutamate receptors activity has been proposed as a promising target for development of rapid-acting antidepressant drugs. In the previous funding period, we investigated Homer1a as modulator of glutamatergic signalling and demonstrated that its antidepressant effects depend on metabotropic glutamate receptor 5 (mGluR5) signaling and enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) function. Moreover, we have introduced a novel approach utilizing systemic administration of cell-penetrable TAT-peptides, which elicit rapid antidepressant effects modulating directly the activity of different glutamatergic receptors.In the present proposal, we plan to further characterize the antidepressant mechanism of action of these TAT-peptides after intranasal application that will allow better brain targeting, enhanced efficacy and clinical validity. Our data suggest that Homer1a-mGluR5 activity differentially affects depression-like behavior, sleep function and synaptic plasticity depending on the brain region and type of neurons targeted. Accordingly, we aim to investigate further the importance of mGluR5 modulation in different brain regions and neuronal population for the homeostatic plasticity, sleep regulation and antidepressant treatment. In addition to regulating glutamatergic signaling within mPFC, Homer1a is also implicated in the modulation of dopaminergic system. Thus, we plan to test the hypothesis that Homer1a affects mood regulation and motivational processing via influencing the dopaminergic signaling within mesolimbic reward circuitry.The ultimate goal of our project is to contribute in the long-run, by better characterization of the molecular and cellular mechanisms of the rapid antidepressant response, to the generation of more selective and efficacious drugs. Moreover, the intranasal application of TAT-peptides targeting glutamatergic system could lead to the development of novel and specific therapeutic strategies for treatment of depression.

抑郁症是最常见的精神疾病。广泛使用的基于单胺的抗抑郁药物需要数周至数月才能改善症状，反应率低，而且经常引起副作用。因此，寻找机制新颖且更有效的抑郁症治疗方案是目前的研究重点。我们已经确定突触可塑性蛋白Homer 1a是抗抑郁治疗的重要组成部分。谷氨酸受体活性的调节已被认为是开发速效抗抑郁药物的一个有前途的靶点。在上一个资助期，我们研究了Homer 1a作为谷氨酸能信号传导的调节剂，并证明其抗抑郁作用依赖于代谢型谷氨酸受体5（mGluR 5）信号传导和增强的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）功能。此外，我们还介绍了一种新的方法，利用全身给药的细胞穿透TAT-肽，引起快速的抗抑郁作用直接调节不同的mammatergic receptor的活性，在本提案中，我们计划进一步表征这些TAT-肽的抗抑郁作用机制鼻内应用后，将允许更好的脑靶向，增强疗效和临床有效性。我们的数据表明，Homer 1a-mGluR 5活性差异影响抑郁样行为，睡眠功能和突触可塑性，这取决于大脑区域和靶向神经元的类型。因此，我们的目标是进一步研究mGluR 5在不同脑区和神经元群体中的调节对于稳态可塑性、睡眠调节和抗抑郁治疗的重要性。除了调节mPFC内的多巴胺能信号外，Homer 1a还参与多巴胺能系统的调节。因此，我们计划验证Homer 1a通过影响中脑边缘奖赏回路中的多巴胺能信号传导来影响情绪调节和动机加工的假设，我们项目的最终目标是通过更好地表征快速抗抑郁反应的分子和细胞机制，为产生更具选择性和有效性的药物做出长期贡献。此外，靶向多巴胺能系统的TAT-肽的鼻内应用可能导致开发用于治疗抑郁症的新的和特异性的治疗策略。