Dual effect of serotonin on the dendritic growth of cultured hippocampal neurons: Involvement of 5-HT1A and 5-HT7 receptors

Abstract

Serotonin acts through its receptors (5-HTRs) to shape brain networks during development and modulates essential functions in mature brain. The 5-HT_1AR is mainly located at soma of hippocampal neurons early during brain development and its expression gradually shifts to dendrites during postnatal development. The 5-HT₇R 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-HT_1AR and 5-HT₇R 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-HT₇R increase significantly at 7 DIV. The 5-HT_1AR is preferentially distributed in the soma, while 5-HT₇R 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-HT_1AR decreases the number of primary and secondary dendrites and restricts the growth of primary dendrites. The activation of 5-HT_1AR and 5-HT₇R 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-HT_1AR restricts dendritogenesis and outgrowth of primary dendrites, but that both 5-HT_1AR and 5-HT₇R 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.

Keywords: 5-HT1AR; 5-HT7R; AKT; Cofilin; Dendrite; ERK1/2; GSK3β; Hippocampal neurons; LIMK; Outgrowth; Serotonin.