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

重度抑郁症是最常见的精神疾病。广泛使用的单胺类抗抑郁药物需要数周到数月才能改善症状，反应率低，而且经常引起副作用。因此，寻找新的机制和更有效的治疗抑郁症的选择是目前的研究重点。我们已经确定突触可塑性蛋白Homer1a是抗抑郁治疗的重要元素。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希望的目标。在之前的资助期内，我们研究了Homer1a作为谷氨酸能信号的调节剂，并证明其抗抑郁作用依赖于代谢性谷氨酸受体5 （mGluR5）信号传导和α-氨基-3-羟基-5-甲基-4-异氧唑丙酸受体（AMPAR）功能的增强。此外，我们已经引入了一种新的方法，利用系统给药细胞可穿透的tat肽，它可以引起快速的抗抑郁作用，直接调节不同谷氨酸受体的活性。在目前的提案中，我们计划进一步表征这些tat -肽鼻内应用后的抗抑郁作用机制，以实现更好的脑靶向，提高疗效和临床有效性。我们的数据表明，Homer1a-mGluR5活性对抑郁样行为、睡眠功能和突触可塑性的影响是不同的，这取决于大脑区域和目标神经元的类型。因此，我们的目标是进一步研究mGluR5在不同脑区和神经元群中的调节在稳态可塑性、睡眠调节和抗抑郁治疗中的重要性。除了调节mPFC内的谷氨酸能信号外，Homer1a还参与多巴胺能系统的调节。因此，我们计划验证Homer1a通过影响中脑边缘奖励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从长远来看，通过更好地表征抗抑郁药快速反应的分子和细胞机制，以产生更具选择性和更有效的药物。此外，靶向谷氨酸系统的tat肽的鼻内应用可能会导致治疗抑郁症的新型和特异性治疗策略的发展。

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.