Disruption of spine homeostasis causes depression

Depression is one of the most burdensome diseases in the world. Although the exact pathogenesis remains unknown, stress is a well-known risk factor for the development of depression. Recently, stress has been known to induce loss of dendritic spines in neurons. Interestingly, also in human brains, higher levels of anxiety and depression scores are associated with decreased densities of spines in the hippocampus, supporting that the disturbance of spine homeostasis is deeply involved in the pathogenesis of depression. On the other hand, general serotonin vulnerability has been also proposed as a major risk factor in depression, where the paucity of available serotonin is involved in the pathogenesis of depression, indicating that the serotonergic system somehow possesses the ability to regulate spine homeostasis. However, the relationship between spine homeostasis and the serotonergic system is largely unknown. Thus, in this manuscript, I try to find the missing link between spine homeostasis and the serotonergic system. The hypothesis is as follows. First, stress reduces the number of spines. Since spine homeostasis is tightly regulated by the serotonergic system, the spine loss is compensated by activated serotonergic system in normal conditions. However, various factors, such as genetic predispositions and heavy stress, decrease the resilience of spine homeostasis. In such conditions, the serotonergic system cannot compensate spine homeostasis anymore, leading to disrupted spine homeostasis. Finally, disrupted spine homeostasis results in depression. The characteristic point of this hypothesis is that it can monistically explain the pathogenesis of depression, where disturbance of spine homeostasis is the main cause.