Serotonin 5‐HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons

Abstract

Precise control of dendritic spine density and synapse formation is critical for normal and pathological brain functions. Therefore, signaling pathways influencing dendrite outgrowth and remodeling remain a subject of extensive investigations. Here, we report that prolonged activation of the serotonin 5-HT7 receptor (5-HT7R) with selective agonist LP-211 promotes formation of dendritic spines and facilitates synaptogenesis in postnatal cortical and striatal neurons. Critical role of 5-HT7R in neuronal morphogenesis was confirmed by analysis of neurons isolated from 5-HT7R-deficient mice and by pharmacological inactivation of the receptor. Acute activation of 5-HT7R results in pronounced neurite elongation in postnatal striatal and cortical neurons, thus extending previous data on the morphogenic role of 5-HT7R in embryonic and hippocampal neurons. We also observed decreased number of spines in neurons with either genetically (i.e. 5-HT7R-knock-out) or pharmacologically (i.e. antagonist treatment) blocked 5-HT7R, suggesting that constitutive 5-HT7R activity is critically involved in the spinogenesis. Moreover, cyclin-dependent kinase 5 and small GTPase Cdc42 were identified as important downstream effectors mediating morphogenic effects of 5-HT7R in neurons. Altogether, our data suggest that the 5-HT7R-mediated structural reorganization during the postnatal development might have a crucial role for the development and plasticity of forebrain areas such as cortex and striatum, and thereby can be implicated in regulation of the higher cognitive functions. Read the Editorial Highlight for this article on page 644.

5‐HT7 receptor shapes spinogenesis in cortical and striatal neurons

“…In this issue of the Journal of Neurochemistry , Speranza and colleagues report effects of the highly potent and selective 5‐HT7R agonist LP‐211 on neurite elongation, and the number of dendritic protrusions and synapses in cultured postnatal murine cortical and striatal neurons (Speranza et al . ). The data are very convincing because the effects are robust and their specificity was verified in experiments using a specific 5‐HT7R antagonist as well as cultures prepared from 5‐HT7R knockout mice.…”

“…Application of the cyclin‐dependent kinase 5 (Cdk5) inhibitor roscovitine (20 μM) or small GTPase cell division cycle 42 (Cdc42) inhibitor ZCL 278 (50 μM) blocked the effects of 5‐HT7R activation (Speranza et al . ). In fact, both drugs reduced the number of spines relative to control, i.e.…”

“…Cultures treated with the specific 5‐HT7R antagonist SB‐269970 as well as cultures derived from 5‐HT7R knockout mice showed similarly reduced levels of dendritic protrusions, as compared to untreated wild‐type cultures, thus suggesting the role of receptor constitutive activity in synapse morphogenesis (Speranza et al . ). This has been previously shown for the growth promoting effects of 5‐HT6R (Duhr et al .…”

“…; Speranza et al . ). Furthermore, the agonist‐independent growth promoting effects of 5‐HT6R required its phosphorylation at a serine residue (Ser 350 ) located in the receptor C‐terminal tail by Cdk5 physically associated with the receptor (Duhr et al .…”

“…The role of 5-HT7R in these processes is unpublished yet but the results presented by Speranza and colleagues uncover two important players mediating the intracellular effects of 5-HT7R on actin cytoskeleton remodelling. Application of the cyclin-dependent kinase 5 (Cdk5) inhibitor roscovitine (20 lM) or small GTPase cell division cycle 42 (Cdc42) inhibitor ZCL 278 (50 lM) blocked the effects of 5-HT7R activation (Speranza et al 2017). In fact, both drugs reduced the number of spines relative to control, i.e.…”