The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways

Speranza, Luisa; Chambery, Angela; Domenico, Marina Di; Crispino, Marianna; Severino, Valeria; Volpicelli, Floriana; Leopoldo, Marcello; Bellenchi, Gian Carlo; Porzio, Umberto di; Perrone-Capano, Carla

doi:10.1016/j.neuropharm.2012.10.026

Cited by 65 publications

(73 citation statements)

References 60 publications

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“…In this work we have first demonstrated that the stimulation of 5-HT7R with the selective agonist LP-211 (Hedlund et al, 2010) leads to enhanced neurite outgrowth in embryonic neuronal primary cultures derived from the cortex (CTX), hippocampus (HIPP) and striatal complex (STR) of embryonic mouse brain corroborating the results that we have previously obtained in rat brain (Speranza et al, 2013). As an extension of this finding, we have herein analyzed several intracellular transduction pathways connecting the stimulation of 5-HT7R to neurite elongation.…”

Section: Introductionsupporting

confidence: 88%

“…Recently we have shown that 5-HT7R activation in neuronal primary cultures from rat brain stimulates neurite outgrowth through Cdk5 and extracellular signal-regulated kinases 1/2 (ERK) pathways, with the modifications of selected cytoskeletal proteins (Speranza et al, 2013), supporting the hypothesis that the 5-HT7R might play a crucial role in shaping neuronal networks during development (Volpicelli et al, 2014). The modulation of connectivity in the nervous system requires remodeling of neuronal morphology and synaptic connections, which in turn depend on dynamic reorganization of cytoskeleton.…”

Section: Introductionmentioning

confidence: 74%

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Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics

Speranza

Giuliano

Volpicelli

et al. 2015

Front. Behav. Neurosci.

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Recent studies have indicated that the serotonin receptor subtype 7 (5-HT7R) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life. Here we show that pharmacological stimulation of 5-HT7R using a highly selective agonist, LP-211, enhances neurite outgrowth in neuronal primary cultures from the cortex, hippocampus and striatal complex of embryonic mouse brain, through multiple signal transduction pathways. All these signaling systems, involving mTOR, the Rho GTPase Cdc42, Cdk5, and ERK, are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth. Indeed, our data indicate that neurite elongation stimulated by 5-HT7R is modulated by drugs affecting actin polymerization. In addition, we show, by 2D Western blot analyses, that treatment of neuronal cultures with LP-211 alters the expression profile of cofilin, an actin binding protein involved in microfilaments dynamics. Furthermore, by using microfluidic chambers that physically separate axons from the soma and dendrites, we demonstrate that agonist-dependent activation of 5-HT7R stimulates axonal elongation. Our results identify for the first time several signal transduction pathways, activated by stimulation of 5-HT7R, that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation. Therefore, the activation of 5-HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development.

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Section: Introductionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 74%

Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics

Speranza

Giuliano

Volpicelli

et al. 2015

Front. Behav. Neurosci.

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“…This result is supported by previous studies in astrocytoma cells showing that serotonin via 5-HT7 receptors can indeed activate p38 MAPK as well as PKC (Lieb et al, 2005). The ability of 5-HT7R to activate the ERK-MAPK pathway has also been demonstrated in cultured neurons expressing endogenous 5-HT7R as well as in cells transiently transfected with 5-HT7R (Errico et al, 2001, Speranza et al, 2013and Speranza et al, 2015. The mechanism by which the 5-HT7 receptors activate ERK1/2 has not been completely elucidated.…”

Section: Mechanismmentioning

confidence: 65%

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

et al. 2016

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The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum

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“…These effects are selectively due to the 5-HT7R stimulation since they are blocked by SB-269970. Neurite elongation requires de novo protein synthesis and is accompanied by qualitative and quantitative modifications of selected cytoskeletal proteins (Speranza et al, 2013). These findings delineate an overall picture of potential intracellular pathways and molecular mechanisms that underlie modulation of neuronal morphology due to 5-HT7R stimulation (Figure 1).…”

Section: The Serotonin Receptor 7 Shapes Neuronal Circuits During Devmentioning

confidence: 99%

The serotonin receptor 7 and the structural plasticity of brain circuits

Volpicelli

Speranza

Porzio

et al. 2014

Front. Behav. Neurosci.

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Serotonin (5-hydroxytryptamine, 5-HT) modulates numerous physiological processes in the nervous system. Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R) in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration.

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The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways

Cited by 65 publications

References 60 publications

Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics

Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

The serotonin receptor 7 and the structural plasticity of brain circuits

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