Enhanced Susceptibility to Chemoconvulsant-Induced Seizures in Ganglioside GM3 Synthase Knockout Mice

Tang, Fu Lei; Wang, Jing; Itokazu, Yukata; Yu, Robert K.

doi:10.1177/1759091420938175

Cited by 8 publications

(5 citation statements)

References 47 publications

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“…The changes reported here are in keeping with the demonstration of hyperactivity in juvenile male St3gal5 −/− mice bred on C57BL/6-129/sv [ 3 , 14 ] and C57BL/6 [ 15 ] backgrounds. The open-field hyperlocomotion of the St3gal5 −/− mutants was also previously reported in juvenile mice of both sexes [ 21 ], which is consistent with our observations here. Niimi et al [ 14 ] found no effect of the administration of psychostimulant methylphenidate on the hyperactivity of juvenile St3gal5 −/− mice.…”

Section: Discussionsupporting

confidence: 93%

“…Current finding suggests that the changes in the EEG of St3gal5 −/− mutants are similar to those observed in the clinic. As St3gal5 −/− mice showed an increased response to the chemoconvulsants pilocarpine, kainate [ 21 ], and pentylenetetrazole [ 16 ], these changes in EEG may indicate vulnerability for these chemoconvulsant-triggered seizures.…”

Section: Discussionmentioning

confidence: 99%

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Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice

et al. 2021

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A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5−/−) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5−/− mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5−/− mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5−/− mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5−/− mice. Together, St3gal5−/− mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice

et al. 2021

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“…Patients with GM3S mutations have symptomatic epilepsy syndrome with severe neuronal dysfunction (Fragaki et al, 2013; Simpson et al, 2004). To investigate how a deficiency of gangliosides is involved in seizure‐susceptibility, we previously induced seizures with chemoconvulsants (including kainate and pilocarpine) in GM3S‐KO mice (Tang et al, 2020) and found enhanced susceptibility to seizure in GM3S‐KO mice compared to wild‐type mice. In the hippocampal DG, loss of GM3 aggravates seizure‐induced aberrant neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis

Fuchigami,

Itokazu,

2023

Glia

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The postnatal neural stem cell (NSC) pool hosts quiescent and activated radial glia‐like NSCs contributing to neurogenesis throughout adulthood. However, the underlying regulatory mechanism during the transition from quiescent NSCs to activated NSCs in the postnatal NSC niche is not fully understood. Lipid metabolism and lipid composition play important roles in regulating NSC fate determination. Biological lipid membranes define the individual cellular shape and help maintain cellular organization and are highly heterogeneous in structure and there exist diverse microdomains (also known as lipid rafts), which are enriched with sugar molecules, such as glycosphingolipids. An often overlooked but key aspect is that the functional activities of proteins and genes are highly dependent on their molecular environments. We previously reported that ganglioside GD3 is the predominant species in NSCs and that the reduced postnatal NSC pools are observed in global GD3‐synthase knockout (GD3S‐KO) mouse brains. The specific roles of GD3 in determining the stage and cell‐lineage determination of NSCs remain unclear, since global GD3S‐KO mice cannot distinguish if GD3 regulates postnatal neurogenesis or developmental impacts. Here, we show that inducible GD3 deletion in postnatal radial glia‐like NSCs promotes NSC activation, resulting in the loss of the long‐term maintenance of the adult NSC pools. The reduced neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of GD3S‐conditional‐knockout mice led to the impaired olfactory and memory functions. Thus, our results provide convincing evidence that postnatal GD3 maintains the quiescent state of radial glia‐like NSCs in the adult NSC niche.

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“…GM3 in turn serves as the precursor for the biosynthesis of numerous other glycolipids, including complex gangliosides that are abundantly found in neuronal tissues. GM3 is enriched in lipid rafts at the plasma membrane and been shown to regulate numerous receptor and integrin‐based signaling pathways 3–8 . Loss of GM3 biosynthesis in GM3SD patients is associated with progressive microcephaly due to impaired neurogenesis, hearing loss, dyskinetic movements, seizures, and variable defects in skin pigmentation 9,10 .…”

Section: Introductionmentioning

confidence: 99%

“…GM3 is enriched in lipid rafts at the plasma membrane and been shown to regulate numerous receptor and integrin-based signaling pathways. [3][4][5][6][7][8] Loss of GM3 biosynthesis in GM3SD patients is associated with progressive microcephaly due to impaired neurogenesis, hearing loss, dyskinetic movements, seizures, and variable defects in skin pigmentation. 9,10 The neuronal manifestations of GM3SD reinforce the importance of ganglioside-mediated processes during neurogenesis, and in the maintenance of proper function of neuronal cell types after development.…”

Section: Introductionmentioning

confidence: 99%

Compound heterozygous variants within two conserved sialyltransferase motifs of ST3GAL5 cause GM3 synthase deficiency

et al. 2022

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GM3 synthase deficiency (GM3SD) is caused by biallelic variants in ST3GAL5. The ganglioside GM3, enriched in neuronal tissues, is a component of lipid rafts and regulates numerous signaling pathways. Affected individuals with GM3SD exhibit global developmental delay, progressive microcephaly, and dyskinetic movements. Hearing loss and altered skin pigmentation are also common. Most of the reported variants in ST3GAL5 are found in motifs conserved across all sialyltransferases within the GT29 family of enzymes. These motifs include motif L and motif S which contain amino acids responsible for substrate binding. These loss-of-function variants cause greatly reduced biosynthesis of GM3 and gangliosides derived from GM3. Here we describe an affected female with typical GM3SD features bearing two novel variants that reside in the other two conserved sialyltransferase motifs (motif 3 and motif VS). These missense alterations occur in amino acid residues that are strictly invariant across the entire GT29 family of sialyltransferases. The functional significance of these variants was confirmed by mass spectrometric analysis of plasma glycolipids, demonstrating a striking loss of GM3 and accumulation of lactosylceramide and Gb3 in the patient. The glycolipid profile changes were accompanied by an increase in ceramide chain length on LacCer. No changes in receptor tyrosine phosphorylation were observed in patient-derived lymphoblasts, indicating that GM3 synthase loss-of-function in this cell type does not impact receptor tyrosine kinase activity. These findings demonstrate the high prevalence of loss-of-function ST3GAL5 variants within highly conserved sialyltransferase motifs in affected individuals with GM3SD.

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Enhanced Susceptibility to Chemoconvulsant-Induced Seizures in Ganglioside GM3 Synthase Knockout Mice

Cited by 8 publications

References 47 publications

Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice

Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice

Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis

Compound heterozygous variants within two conserved sialyltransferase motifs of ST3GAL5 cause GM3 synthase deficiency

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