GD3 synthase gene knockout mice exhibit thermal hyperalgesia and mechanical allodynia but decreased response to formalin-induced prolonged noxious stimulation

Abstract

Gangliosides are a family of sialic acid-containing glycosphingolipids that are highly enriched in the mammalian nervous system. In particular, b- and c-series gangliosides, all of which contain alpha-2,8 sialic acids, have been considered to play important roles in adhesion, toxin-binding, neurite extension, cell growth and apoptosis. However, the neurobiological functions of these series of gangliosides remain largely unknown. To clarify the function of b- and c-series gangliosides in pain sensation in vivo, we generated mice in whom the gene for the alpha-2,8-sialyltransferase (GD3 synthase), which is responsible for the generation of all b-series gangliosides as well as c-series gangliosides, was disrupted. Compared to the wild-type mice, the mutant mice exhibited increased sensory responses to thermal and mechanical stimuli as measured by a hot plate test and von Frey test. In contrast, the mutant mice showed decreased responses during the late phase of the formalin test. Paw edema and Fos expression in the spinal cord after formalin injection were significantly decreased in the mutant mice compared to the wild-type mice. No significant differences in the conduction velocity of the sciatic nerve, and no apparent morphologic differences in the spinal cord and the sciatic nerve were detected between the wild-type and the mutant mice. These results suggested that b- and c-series gangliosides are critical in the development and/or maintenance of the sensory nervous system responsible for the transmission of acute pain sensation and pain modulation. Moreover, they play an important role in the development of hyperalgesia induced by inflammation.

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

“…Another relevant factor, the size of the pool of synaptic vesicles ready for release, is not likely to be influenced by gangliosides, because we did not find differences between genotypes when we assessed for this parameter with hypertonic stimulation (Stevens and Tsujimoto, 1995;Varoqueaux et al, 2005), either here at aged NMJs or previously in younger ones (Zitman et al, 2008). The less steep relationship between extracellular Ca 2+ and evoked ACh release observed at NMJs of old GD3s-KO mice (and seen previously in young ones) may also be due to altered Ca 2+ buffering or membrane flux, possibly resulting from a progressive increase in GM1 density due to accumulation of O-and/or a-series gangliosides (Handa et al, 2005;Okada et al, 2002). This may also explain the higher MEPP frequency at GD3s-KO NMJs in 0.2 and 2 mM extracellular Ca 2+ .…”

“…Gangliosides are present in the vicinity of AChRs (Pato et al, 2008) and can interact with the protein, as shown for AChR-rich membrane from Torpedo marmorata (Mantipragada et al, 2003). Accumulation of O-and/or a-series gangliosides may occur at muscle membranes of GD3s-KO mice, as it does at neuronal membranes (Handa et al, 2005;Okada et al, 2002), and progressiveness of this process may lead to the observed age-specific changes in EPP kinetics. EPP rise time and halfwidth are highly temperaturedependent parameters (Fig.…”

“…Alternatively, they might be caused by accumulation of the remaining ganglioside sub-sets, amounting to neurotoxic levels during ageing. Brains of GM2s-KO mice accumulate GM3 and GD3 ganglioside (Kawai et al, 2001;Takamiya et al, 1996), while those of GD3s-KO mice accumulate a-series gangliosides (Handa et al, 2005; and possibly also O-series gangliosides. Brains of compound null-mutants have increased GM3 expression Kawai et al, 2001).…”

Functional Diversity of Mammalian Sialyltransferases

“…Nonetheless, they exhibit reduced regeneration of axotomized hypoglossal nerves as compared to wild-type mice. In addition, ST8Sia-I knockout mice exhibit increased sensory responses to thermal and mechanical stimuli and decreased responses during the late phase of the formalin injection test (115). This suggests that b-and c-series gangliosides are critical in the repair and functional maintenance of the nervous system.…”

Characterization of Mouse Sialyltransferase Genes: Their Evolution and Diversity

“…In addition, ST8Sia I knockout mice exhibited increased sensory responses to thermal and mechanical stimuli and decreased responses during the late phase of a formalin injection test. 59) This suggests that b-and c-series gangliosides are critical in the development, maintenance, and repair of the nervous system. Double knockout mice lacking the GM2/GD2 synthase and GD3 synthase genes, which express only the GM3 ganglioside, exhibited lethal audiogenic seizures.…”