The interplay of serotonin 5-HT1A and 5-HT7 receptors in chronic stress.

Serotonin regulates multiple physiological and pathological processes in the brain, including mood and cognition. Serotonin receptors 5-HT1AR and 5-HT7R have emerged as key players in stress-related disorders, particularly depression. These receptors can form heterodimers, which influence their functions. Here we explored the developmental dynamics of 5-HT1AR and 5-HT7R expression and validated heterodimerization levels in the brain of control and stressed mice. In control animals, we obtained increase in 5-HT1AR expression over 5-HT7R in the prefrontal cortex (PFC) and hippocampus during development. Using a chronic unpredictable stress as a depression model, we found increase in 5-HT7R expression exclusively in the PFC of resilient animals, while no changes in 5-HT1AR expression between control and anhedonic mice were obtained. Quantitative in situ analysis of heterodimerization revealed the PFC as region exhibiting the highest abundance of 5-HT1AR/5-HT7R heterodimers. More importantly, upon chronic stress amount of heterodimers was significantly reduced only in PFC of anhedonic mice, while it was not affected in resilient animals. These results suggest an important role of brain-region specific 5-HT1AR/5-HT7R heterodimerization for establishing depressive-like behavior and for development of resiliency.