LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor

Hedlund, Peter B.; Leopoldo, Marcello; Caccia, Silvio; Sarkisyan, Gor; Fracasso, Claudia; Martelli, Giuliana; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto

doi:10.1016/j.neulet.2010.06.036

Cited by 69 publications

(85 citation statements)

References 25 publications

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“…Thus, in the present study we examined the effect of a specific 5-HT7R agonist on the PF-PC synapse in cerebellar slices of adult mice. The results presented here show that activation of 5-HT7R by the selective agonist LP-211 (Hedlund et al, 2010), produces a long-lasting synaptic depression between parallel fibers and Purkinje cells. Such depression is postsynaptically expressed and requires the activation of protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) signaling pathways.…”

Section: Introductionmentioning

confidence: 56%

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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Section: Introductionmentioning

confidence: 56%

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

et al. 2016

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“…LP-211 has been found to induce hypothermia in in mice. The hypothermic effect could be inhibited by SB-269970, but not WAY-100135, and was absent in 5-HT 7 receptor knockout animals (Hedlund et al, 2010). Interestingly, the 5-HT 7 receptor seems to be most important at low agonist concentrations, thus contributing to the fine-tuning of temperature homeostasis, whereas the 5-HT 1A receptor comes into play at higher agonist concentrations possibly providing a defense against hyperthermia (Hedlund et al, 2004).…”

Section: 5-ht7 Receptor Function In Normal and Pathological Processesmentioning

confidence: 96%

Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders

Leopoldo

Lacivita

Berardi

et al. 2011

Pharmacology & Therapeutics

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Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented.

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“…Administration of 5-HT 7 receptor agonists induced hypothermia in wild type guinea pigs and mice (Hagan et al, 2000; Guscott et al, 2003; Hedlund et al, 2003, 2010) but not in 5-HT 7 KO mice (Guscott et al, 2003; Hedlund et al, 2003). …”

Section: Physiological Functions Regulated By 5-ht7 Receptorsmentioning

confidence: 99%

5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

Ciranna

Catania

2014

Front. Cell. Neurosci.

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Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD.

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LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor

Cited by 69 publications

References 25 publications

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

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

Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders

5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

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