Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders: from molecular mechanisms to behavioral regulation.

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Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological functions within the central nervous system via activation of heterogeneously expressed 5-HT receptors. Serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are critically implicated in major depressive disorder (MDD), although underlying mechanisms remain enigmatic. Functional studies have also implicated 5-HT7Rs in depression. Since 5-HT1A and 5-HT7 receptors are co-expressed in majority of the brain structures and modulate the same second messenger systems, one intriguing question is the possible functional cross-talk between these receptors under physiological and pathological conditions.We have previously shown that the 5-HT1AR forms homo-dimers as well as hetero-dimers with the 5-HT7R. Functionally, hetero-dimerization inhibits coupling of 5-HT1AR to Gi proteins, attenuates 5-HT1AR-mediated activation of potassium channels and facilitates internalization of 5-HT1AR, without affecting 5-HT7R signaling. Moreover, we developed FRET-based approaches for simultaneous analysis of receptor oligomerization and receptor-mediated signaling at the single-cell levels. We also demonstrated co-expression of 5-HT1A and 5-HT7 receptors in serotonergic raphe neurons, suggesting an important role of hetero-dimerization in functional regulation of the 5-HT1A autoreceptor. Finally, we constructed a set of adenoviral vectors to manipulate expression of 5-HT1AR and 5-HT7R in vivo. We hypothesize that regulated and balanced ratio of homo- and hetero-dimerization on pre- and postsynaptic neurons may be critically involved in both the onset as well as the response to treatment of MDD. The main scientific question of the present proposal is thus how 5-HT1AR/5-HT7R hetero-dimerization modulates receptor-mediated signaling, including receptor desensitization and activation of the down-stream effectors in different types of neurons under physiological and pathological conditions. The second goal is to elucidate the functional role of hetero-dimerization in the development, maintenance and pathogenesis of depression-like symptoms. To achieve these goals we will apply a synergistic combination of innovative techniques (e.g. analysis of hetero-dimerization in the mouse brain, quantitative microscopy, FRET, electrophysiological recordings, application of different depression models in rodents, and behavioral analysis). To validate the role of hetero-dimerization in human MDD, we will investigate the post-mortem samples from suicide victims diagnosed previously with major depression and control subjects. The combined outcomes of these investigations will greatly advance our fundamental knowledge about the impact of GPCR oligomerization on regulation of neuronal functions under physiological and pathological conditions, providing information about the possible therapeutic role of 5-HT1AR/5-HT7R hetero-dimerization for treating depression.