Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2

Akahoshi, Noriyuki; Ishizaki, Yasuki; Yasuda, Hiroki; Murashima, Yoshiya L.; Shinba, Toshikazu; Goto, Kaoru; Himi, Toshiyuki; Chun, Jerold; Ishii, Isao

doi:10.1016/j.yebeh.2011.09.002

Cited by 32 publications

(24 citation statements)

References 36 publications

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“…Another target of FTY720, S1P 3 , was also found on reactive astrocytes in human MS lesions and upregulated by lipopolysaccharide stimulation of astrocytes in vitro, although it is unknown if expression of S1P 3 is protective or pathogenic in the context of MS/EAE ( 147 ). Mice deficient in the one S1PR not targeted by FTY720, S1P 2 , are prone to seizures resulting in 40% mortality and have enhanced hippocampal gliosis accompanied by behavioral defects ( 148 ). Importantly, MS patients treated with fi ngolimod show reduced brain volume loss and lesional activity, suggesting the importance of S1PR pathways in neuroprotection (149)(150)(151).…”

Section: Nervous Systemmentioning

confidence: 99%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

438

403

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This article is available online at http://www.jlr.org during development and ageing. S1P 1 , S1P 2 , and S1P 3 are essentially ubiquitously expressed, whereas expression of S1P 4 and S1P 5 are highly restricted to distinct cell types ( 4 ).Production of S1P can be initiated by external or internal signals, which lead to activation of the biosynthetic pathway beginning with metabolism of membrane SM to ceramide by SMases ( 5, 6 ). Ceramide, an important signaling molecule itself, can be metabolized by ceramidase to sphingosine (Sph) ( 7 ). Sph is then phosphorylated by one of two Sph kinases (Sphks), Sphk1 or Sphk2, resulting in S1P genesis ( 8-10 ) ( Fig. 1 ).Although there are proposed intracellular roles for S1P, it is often transported out of the cell where it can act in an autocrine or paracrine manner on S1PRs ( 11, 12 ). Transport out of the cell may occur via several transporters; however, the only bona fi de transporter to date is spinster 2, which is also capable of FTY720 (fi ngolimod/Gilenya; Novartis) export (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Once outside of the cell, S1P can bind to two known carriers, albumin or ApoM ( 6, 23, 24 ) ( Fig. 1 ). Approximately 35% of plasma S1P is bound to albumin and 65% to ApoM, which is found on a small percentage ( ‫ف‬ 5%) of HDL particles ( 24 ). This ApoM+HDL-bound S1P has been proposed as a primary contributor to the vasoprotective properties of HDLs ( 25-27 ). How albumin or ApoM deliver S1P to specifi c S1PRs has yet to be characterized. AGONISTS AND ANTAGONISTSThere are several well-characterized agonists and antagonists of S1PRs; however, most compounds have been diAbstract Sphingosine 1-phosphate (S1P) is a membranederived lysophospholipid that acts primarily as an extracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P 1-5 . Cellular and temporal expression of the S1P receptors (S1PRs) determine their specifi c roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte traffi cking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic infl ammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater effi cacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs. Sphingosine 1-phosphate [2 S -amino-1-(dihydrogen phosphate)-4E-octadecene-1,3 R -diol] (S1P) is a simple membrane-derived lysophospholipid with regulatory roles in almost all facets of mammalian biology ( 1 ). Concentrations of S1P in blood and lymph plasmas are high, in the high...

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Section: Nervous Systemmentioning

confidence: 99%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

438

403

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“…Consequently, LPA and S1P signaling affects CNS cell types such as neuroblasts, neurons, astrocytes, and oligodendrocytes to influence cell survival, proliferation, migration, differentiation, and morphological changes (reviewed in [1,3,8–11]). To date, LPA and/or S1P receptors have been identified as important factors in CNS development, as well as having roles in diseases, including MS [12,13], fetal hypoxia and hydrocephalus [14–16], neuropathic pain [17–19], brain ischemic stroke [20,21], neurotrauma [22], developmental disorders like schizophrenia, as well as hearing loss [23–25], seizures [26–28], and Sandhoff disease [29]. …”

Section: Introductionmentioning

confidence: 99%

Lysophospholipids and their receptors in the central nervous system

Choi

Chun

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including organismal development as well as function and pathogenesis within multiple organ systems. These functional roles are due to a family of at least 11 G protein-coupled receptors (GPCRs), named LPA1–6 and S1P1–5, which are widely distributed throughout the body and that activate multiple effector pathways initiated by a range of heterotrimeric G proteins including Gi/o, G12/13, Gq and Gs, with actual activation dependent on receptor subtypes. In the central nervous system (CNS), a major locus for these signaling pathways, LPA and S1P have been shown to influence myriad responses in neurons and glial cell types through their cognate receptors. These receptor-mediated activities can contribute to disease pathogenesis and have therapeutic relevance to human CNS disorders as demonstrated for multiple sclerosis (MS) and possibly others that include congenital hydrocephalus, ischemic stroke, neurotrauma, neuropsychiatric disorders, developmental disorders, seizures, hearing loss, and Sandhoff disease, based upon the experimental literature. In particular, FTY720 (fingolimod, Gilenya, Novartis Pharma, AG) that becomes an analog of S1P upon phosphorylation, was approved by the FDA in 2010 as a first oral treatment for MS, validating this class of receptors as medicinal targets. This review will provide an overview and update on the biological functions of LPA and S1P signaling in the CNS, with a focus on results from studies using genetic null mutants for LPA and S1P receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

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“…Mechanisms of memory formation are most extensively studied in the hippocampus where SphK1 expression levels are high exclusively within hippocampal mossy fibers (Kanno et al, 2010) whereas Sphk2 and S1p 2 mRNA are expressed in the CA1–CA3 regions (Blondeau et al, 2007; Akahoshi et al, 2011; Kempf et al, 2014). Involvement of S1P 1 in memory formation has not yet been demonstrated and mice with a global depletion of S1P 1 are embryonically lethal (Liu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…

{S1P}_{3}^{- / -}

mice show signatures of augmented anxiety in the open field test and display a spatial working memory deficit in the eight arm radial maze, but no change in LTP formation at Schaffer collateral—CA1 synapses (Akahoshi et al, 2011). Interestingly though, inhibition of S1P 2 leads to an increase in Schaffer collateral—CA1 LTP and a similar effect is observed when the newly discovered endogenous S1P 2 ligand Nogo-A is neutralized (Kempf et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In neurons, S1P receptor signaling has been connected to proliferation, survival, and apoptosis, neurite extension, and retraction, excitability and neurotransmitter release (Okada et al, 2009). Furthermore, S1P signaling has been associated with learning and memory within the hippocampus (Kajimoto et al, 2007; Kanno et al, 2010; Akahoshi et al, 2011; Kanno and Nishizaki, 2011; Antonucci et al, 2012; Riganti et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Ablation of Sphingosine 1-Phosphate Receptor Subtype 3 Impairs Hippocampal Neuron Excitability In vitro and Spatial Working Memory In vivo

Weth-Malsch

Langeslag

Beroukas

et al. 2016

Front. Cell. Neurosci.

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Understanding the role of the bioactive lipid mediator sphingosine 1-phosphate (S1P) within the central nervous system has recently gained more and more attention, as it has been connected to major diseases such as multiple sclerosis and Alzheimer's disease. Even though much data about the functions of the five S1P receptors has been collected for other organ systems, we still lack a complete understanding for their specific roles, in particular within the brain. Therefore, it was the aim of this study to further elucidate the role of S1P receptor subtype 3 (S1P3) in vivo and in vitro with a special focus on the hippocampus. Using an S1P3 knock-out mouse model we applied a range of behavioral tests, performed expression studies, and whole cell patch clamp recordings in acute hippocampal slices. We were able to show that S1P3 deficient mice display a significant spatial working memory deficit within the T-maze test, but not in anxiety related tests. Furthermore, S1p3 mRNA was expressed throughout the hippocampal formation. Principal neurons in area CA3 lacking S1P3 showed significantly increased interspike intervals and a significantly decreased input resistance. Upon stimulation with S1P CA3 principal neurons from both wildtype and S1P3−/− mice displayed significantly increased evoked EPSC amplitudes and decay times, whereas rise times remained unchanged. These results suggest a specific involvement of S1P3 for the establishment of spatial working memory and neuronal excitability within the hippocampus.

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Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2

Cited by 32 publications

References 36 publications

An update on the biology of sphingosine 1-phosphate receptors

An update on the biology of sphingosine 1-phosphate receptors

Lysophospholipids and their receptors in the central nervous system

Ablation of Sphingosine 1-Phosphate Receptor Subtype 3 Impairs Hippocampal Neuron Excitability In vitro and Spatial Working Memory In vivo

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