抑郁症的日益频发是精神卫生领域的重要挑战。研究证实水通道蛋白4（AQP4）与动物抑郁样行为及欣快行为相关，但具体机制尚不明确。我们研究已证实前额叶皮层-伏隔核神经环路中NMDA受体功能下调并发突触可塑性损害在抑郁症中发挥重要作用。前期预实验我们发现AQP4敲除动物社会接触行为减少，其行为改变可能与前额叶皮层-伏隔核神经环路NMDA受体依赖的长时程削弱受损相关。鉴此，我们推测：下调伏隔核区AQP4将通过增强该神经环路内NMDA受体功能，改善抑郁模型的突触功能及行为表现。本项目拟建立慢性社会挫败及慢性轻度不可预见应激模型，采用行为学、神经电生理和分子生物学、慢病毒干预等技术，研究①抑郁模型各神经环路内AQP4表达变化；②AQP4下降在模型鼠NMDA受体功能下调中的作用；③神经环路调节AQP4水平对动物抑郁样行为的影响。本研究有助于揭示AQP4通道蛋白在抑郁症发病中的作用。

Major depression is a common, recurrent and serious mental illness that affects millions of people worldwide. Aquaporins (AQPs) are a family of membrane channels that play a significant role in regulating water homeostasis. A lot of evidence shows that AQP4 is involved in the pathophysiology of cerebral disorders, including neuro-optic myelitis, cerebral edema, stroke, traumatic brain injury, epilepsy, and depression, and so on. Our preliminary experiments have found that AQP4 knockout (KO) mice displayed significantly decreased social interaction, compared with control normal mice. We also demonstrated that Aquaporin-4 (AQP4) deficiency selectively impaired long-term depression (LTD) in the cortico-accumbal glutamatergic synapse, which may underlie the behavioral effects of AQP4 deficiency. Our team has identified NMDA receptors in the prefrontal cortex-nucleus accumbens circuit as a key regulator in the modulation of persistent psychomotor plasticity in major depression animal model. However, the mechanisms underlying this effect of NMDA receptors have not been investigated. Therefore, we proposed that decreased brain AQP4 might contribute to the hypofunction of NMDARs and the onset of behavioral disorders in depression, and regulating brain AQP4 would improve the behavioral performances via enhancing NMDARs function. Chronic social defeat stress and chronic unpredictable mild stress models will be used to evaluate the relation between AQP4 in the nucleus accumbens and major depression. Based on these evidences, we are going to use various methods, including behavioral, electrophysiological, biochemical and molecular biological techniques and lentiviral-gene interference to explore: 1) the amount and activity of AQP4 in the NAc extract in the pathogenesis of major depression; 2) AQP4 regulates the function and expression of NMDA receptors in the NAc of major depression animals; 3) AQP4 in the NAc regulates behavioral performance in animal models of depression. We hope to reveal the role of AQP4 in the pathogenesis of major depression, providing new information for the pathophysiology of depression and proposing a new strategy for the treatment of depression.