Dual effect of serotonin on the dendritic growth of cultured hippocampal neurons: Involvement of 5-HT and 5-HT receptors.

Serotonin acts through its receptors (5-HTRs) to shape brain networks during development and modulates essential functions in mature brain. The 5-HTR is mainly located at soma of hippocampal neurons early during brain development and its expression gradually shifts to dendrites during postnatal development. The 5-HTR expressed early during hippocampus development, shows a progressive reduction in its expression postnatally. Considering these changes during development, we evaluated in cultured hippocampal neurons whether the 5-HTR and 5-HTR change their expression, modulate dendritic growth, and activate signaling pathways such as ERK1/2, AKT/GSK3β and LIMK/cofilin, which may sustain dendrite outgrowth by controlling cytoskeleton dynamics. We show that mRNA levels of both receptors increase between 2 and 7 DIV; however only protein levels of 5-HTR increase significantly at 7 DIV. The 5-HTR is preferentially distributed in the soma, while 5-HTR displays a somato-dendritic localization at 7 DIV. Through stimulation with 5-HT at 7 DIV during 24h and using specific antagonists, we determined that 5-HTR decreases the number of primary and secondary dendrites and restricts the growth of primary dendrites. The activation of 5-HTR and 5-HTR promotes the growth of short secondary dendrites and triggers ERK1/2 and AKT phosphorylation through MEK and PI3K activation respectively; without changes in the phosphorylation of LIMK and cofilin. We conclude that 5-HTR restricts dendritogenesis and outgrowth of primary dendrites, but that both 5-HTR and 5-HTR promote secondary dendrite outgrowth. These data support the role of 5-HT in neuronal outgrowth during development and provide insight into cellular basis of neurodevelopmental disorders.