5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits

5-HT6 receptor (5-HT6R) is a G protein-coupled receptor that has recently emerged as a new regulator of neural development. In addition to the canonical Gs adenylyl cyclase pathway, recent proteomics approaches reveal that 5-HT6R is able to engage key developmental signaling pathways controlling neuronal circuit formation, neuronal connectivity, and psychiatric-relevant behaviors. For example, at early stages of neuronal development, expression of 5-HT6R constitutively regulates the activity of the cyclin-dependent kinase (Cdk)5 and, through this mechanism, controls cellular processes involved in circuit formation, including neuronal migration and neurite outgrowth. In addition to the Cdk5 pathway, 5-HT6R modulates a variety of key developmental targets such as Fyn, Jab1, and mammalian target of rapamycin (mTOR). Engagement of developmental pathways through 5-HT6R pharmacological manipulation has led to interesting new therapeutic perspectives in the field of psychiatric-related disorders. Indeed, 5-HT6R blockade can rescue a pathological overactivation of the mTOR pathway induced by early life insults in rodents and normalizes the associated social and episodic memory deficits. Here, we review recent evidence supporting the notion that 5-HT6R is at the interface of key developmental signaling pathways and a novel actor in the orchestration of neural circuit formation.