Advertisement

Neurochemical Research

, 34:1057 | Cite as

Brain Lipid Analysis in Mice with Rett Syndrome

  • Thomas N. SeyfriedEmail author
  • Karie A. Heinecke
  • John G. Mantis
  • Christine A. Denny
Original Paper

Abstract

Rett syndrome (RS) is an X-linked neurodevelopmental disorder mostly involving mutations in the gene for methyl-CpG-binding protein 2 (MECP2). Ganglioside abnormalities were previously found in cerebrum and cerebellum in RS patients. We evaluated total lipid distribution in cerebrum/brainstem, hippocampus, and cerebellum in male mice carrying either the Mecp2 tm1.1Bird knockout mutation or the Mecp2 308/y deletion mutation. The concentration of the neuronal enriched ganglioside GD1a was significantly lower in the cerebrum/brainstem of Mecp2 tm1.1Bird mice than in that of age matched controls, but was not reduced in the Mecp2 308/y mice. No other differences in brain lipid content, including myelin-enriched cerebrosides, were detected in mice with either type of Mecp2 mutation. These findings indicate that the poor motor performance previously reported in the RS mutant mice is not associated with major brain lipid abnormalities and that most previous brain lipid abnormalities observed in RS patients were not observed in the Mecp2 tm1.1Bird or the Mecp2 308/y RS mice.

Keywords

Mecp2 Rett Mouse models Gangliosides GD1a Myelin 

Notes

Acknowledgements

This work was supported in part from NIH grant (NS055195), the Rett Syndrome Research Foundation (RSRF) and the Boston College Research Expense Fund. We would like to thank Dr. Zhaolan Zhou and Dr. Michael Greenberg (Children’s Hospital Boston, Harvard Medical School) for providing us with the Mecp2 Bird mice used in our study. We also thank Nicholas C. Zimick and Christie L. Fritz for helping with the breeding and genotyping of the mice.

References

  1. 1.
    Shahbazian M, Young J, Yuva-Paylor L et al (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35:243–254. doi: 10.1016/S0896-6273(02)00768-7 PubMedCrossRefGoogle Scholar
  2. 2.
    Hagberg B, Aicardi J, Dias K et al (1983) A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 14:471–479. doi: 10.1002/ana.410140412 PubMedCrossRefGoogle Scholar
  3. 3.
    Percy AK (2002) Rett syndrome. Current status and new vistas. Neurol Clin 20:1125–1141. doi: 10.1016/S0733-8619(02)00022-1 PubMedCrossRefGoogle Scholar
  4. 4.
    Amir RE, Van den Veyver IB, Wan M et al (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188. doi: 10.1038/13810 PubMedCrossRefGoogle Scholar
  5. 5.
    Chahrour M, Jung SY, Shaw C et al (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224–1229. doi: 10.1126/science.1153252 PubMedCrossRefGoogle Scholar
  6. 6.
    Guy J, Hendrich B, Holmes M et al (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326. doi: 10.1038/85899 PubMedCrossRefGoogle Scholar
  7. 7.
    Percy AK, Lane JB (2004) Rett syndrome: clinical and molecular update. Curr Opin Pediatr 16:670–677. doi: 10.1097/01.mop.0000143693.59408.ce PubMedCrossRefGoogle Scholar
  8. 8.
    Samaco RC, Nagarajan RP, Braunschweig D et al (2004) Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 13:629–639. doi: 10.1093/hmg/ddh063 PubMedCrossRefGoogle Scholar
  9. 9.
    Lekman A, Hagberg B, Svennerholm L (1991) Altered cerebellar ganglioside pattern in Rett syndrome. Neurochem Int 19:505–509. doi: 10.1016/0197-0186(91)90068-O CrossRefGoogle Scholar
  10. 10.
    Lekman AY, Hagberg BA, Svennerholm LT (1991) Membrane cerebral lipids in Rett syndrome. Pediatr Neurol 7:186–190. doi: 10.1016/0887-8994(91)90082-V PubMedCrossRefGoogle Scholar
  11. 11.
    Lekman AY, Hagberg BA, Svennerholm LT (1999) Cerebrospinal fluid gangliosides in patients with Rett syndrome and infantile neuronal ceroid lipofuscinosis. Eur J Paediatr Neurol 3:119–123. doi: 10.1016/S1090-3798(99)90099-5 PubMedCrossRefGoogle Scholar
  12. 12.
    Papadimitriou JM, Hockey A, Tan N et al (1988) Rett syndrome: abnormal membrane-bound lamellated inclusions in neurons and oligodendroglia. Am J Med Genet 29:365–368. doi: 10.1002/ajmg.1320290216 PubMedCrossRefGoogle Scholar
  13. 13.
    Oldfors A, Sourander P, Armstrong DL et al (1990) Rett syndrome: cerebellar pathology. Pediatr Neurol 6:310–314. doi: 10.1016/0887-8994(90)90022-S PubMedCrossRefGoogle Scholar
  14. 14.
    Norton WT (1977) Isolation and characterization of myelin. In: Morell P (ed) Myelin. Plenum, New York, pp 161–199Google Scholar
  15. 15.
    Muse ED, Jurevics H, Toews AD et al (2001) Parameters related to lipid metabolism as markers of myelination in mouse brain. J Neurochem 76:77–86. doi: 10.1046/j.1471-4159.2001.00015.x PubMedCrossRefGoogle Scholar
  16. 16.
    Belichenko NP, Belichenko PV, Li HH et al (2008) Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome. J Comp Neurol 508:184–195. doi: 10.1002/cne.21673 PubMedCrossRefGoogle Scholar
  17. 17.
    Viola A, Saywell V, Villard L et al (2007) Metabolic fingerprints of altered brain growth, osmoregulation and neurotransmission in a Rett syndrome model. PLoS ONE 2:e157. doi: 10.1371/journal.pone.0000157 PubMedCrossRefGoogle Scholar
  18. 18.
    Svennerholm L, Bostrom K, Fredman P et al (1989) Human brain gangliosides: developmental changes from early fetal stage to advanced age. Biochim Biophys Acta 1005:109–117PubMedGoogle Scholar
  19. 19.
    Seyfried TN, Bernard DJ, Yu RK (1984) Cellular distribution of gangliosides in the developing mouse cerebellum: analysis using the staggerer mutant. J Neurochem 43:1152–1162. doi: 10.1111/j.1471-4159.1984.tb12856.x PubMedCrossRefGoogle Scholar
  20. 20.
    Seyfried TN, Yu RK (1984) Cellular localization of gangliosides in the mouse cerebellum: analysis using neurological mutants. Adv Exp Med Biol 174:169–181PubMedGoogle Scholar
  21. 21.
    Seyfried TN, Yu RK (1985) Ganglioside GD3: structure, cellular distribution, and possible function. Mol Cell Biochem 68:3–10PubMedGoogle Scholar
  22. 22.
    Seyfried TN, Miyazawa N, Yu RK (1983) Cellular localization of gangliosides in the developing mouse cerebellum: analysis using the weaver mutant. J Neurochem 41:491–505. doi: 10.1111/j.1471-4159.1983.tb04767.x PubMedCrossRefGoogle Scholar
  23. 23.
    Seyfried TN, Yu RK (1990) Cerebellar ganglioside abnormalities in pcd mutant mice. J Neurosci Res 26:105–111. doi: 10.1002/jnr.490260113 PubMedCrossRefGoogle Scholar
  24. 24.
    Seyfried TN, Yu RK, Miyazawa N (1982) Differential cellular enrichment of gangliosides in the mouse cerebellum: analysis using neurological mutants. J Neurochem 38:551–559. doi: 10.1111/j.1471-4159.1982.tb08662.x PubMedCrossRefGoogle Scholar
  25. 25.
    Seyfried TN, Bernard D, Mayeda F et al (1984) Genetic analysis of cerebellar lipids in mice susceptible to audiogenic seizures. Exp Neurol 84:590–595. doi: 10.1016/0014-4886(84)90206-1 PubMedCrossRefGoogle Scholar
  26. 26.
    Seyfried TN, Yu RK (1980) Heterosis for brain myelin content in mice. Biochem Genet 18:1229–1238. doi: 10.1007/BF00484350 PubMedCrossRefGoogle Scholar
  27. 27.
    Kiebish MA, Han X, Cheng H et al (2008) Lipidomic analysis and electron transport chain activities in C57BL/6J mouse brain mitochondria. J Neurochem 106:299–312. doi: 10.1111/j.1471-4159.2008.05383.x PubMedCrossRefGoogle Scholar
  28. 28.
    Seyfried TN, Glaser GH, Yu RK (1978) Developmental analysis of regional brain growth and audiogenic seizures in mice. Genetics 88:S90Google Scholar
  29. 29.
    Kasperzyk JL, El-Abbadi MM, Hauser EC et al (2004) N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis. J Neurochem 89:645–653. doi: 10.1046/j.1471-4159.2004.02381.x PubMedCrossRefGoogle Scholar
  30. 30.
    Baek RC, Kasperzyk JL, Platt FM et al (2008) N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice. Neurochem Int 52:1125–1133. doi: 10.1016/j.neuint.2007.12.001 PubMedCrossRefGoogle Scholar
  31. 31.
    Macala LJ, Yu RK, Ando S (1983) Analysis of brain lipids by high performance thin-layer chromatography and densitometry. J Lipid Res 24:1243–1250PubMedGoogle Scholar
  32. 32.
    Kasperzyk JL, d’Azzo A, Platt FM et al (2005) Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice. J Lipid Res 46:744–751. doi: 10.1194/jlr.M400411-JLR200 PubMedCrossRefGoogle Scholar
  33. 33.
    Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509PubMedGoogle Scholar
  34. 34.
    Svennerholm L (1957) Quantitative estimation of sialic acids II. A colorimetric resorcinol-hydrochloric acid method. Biochim Biophys Acta 24:604–611. doi: 10.1016/0006-3002(57)90254-8 PubMedCrossRefGoogle Scholar
  35. 35.
    Hauser EC, Kasperzyk JL, d’Azzo A et al (2004) Inheritance of lysosomal acid beta-galactosidase activity and gangliosides in crosses of DBA/2J and knockout mice. Biochem Genet 42:241–257. doi: 10.1023/B:BIGI.0000034429.55418.71 PubMedCrossRefGoogle Scholar
  36. 36.
    Ando S, Chang NC, Yu RK (1978) High-performance thin-layer chromatography and densitometric determination of brain ganglioside compositions of several species. Anal Biochem 89:437–450. doi: 10.1016/0003-2697(78)90373-1 PubMedCrossRefGoogle Scholar
  37. 37.
    Seyfried TN, Glaser GH, Yu RK (1978) Cerebral, cerebellar, and brain stem gangliosides in mice susceptible to audiogenic seizures. J Neurochem 31:21–27. doi: 10.1111/j.1471-4159.1978.tb12428.x PubMedCrossRefGoogle Scholar
  38. 38.
    Sato C, Yu RK (1987) Myelin galactolipid synthesis in different strains of mice. J Neurochem 49:1069–1074. doi: 10.1111/j.1471-4159.1987.tb09995.x PubMedCrossRefGoogle Scholar
  39. 39.
    Morell P, Quarles RH (1999) Myelin formation, structure and biochemistry. In: Siegel GJ et al (eds) Basic neurochemistry. Lippincott-Raven, New York, pp 69–93Google Scholar
  40. 40.
    Brigande JV, Wieraszko A, Albert MD et al (1992) Biochemical correlates of epilepsy in the E1 mouse: analysis of glial fibrillary acidic protein and gangliosides. J Neurochem 58:752–760. doi: 10.1111/j.1471-4159.1992.tb09782.x PubMedCrossRefGoogle Scholar
  41. 41.
    Yusuf HKM, Dickerson JWT (1978) Disialoganglioside GD1a of rat brain subcellular particles during development. Biochem J 174:655–657PubMedGoogle Scholar
  42. 42.
    Levine SM, Seyfried TN, Yu RK et al (1986) Immunocytochemical localization of GD3 ganglioside to astrocytes in murine cerebellar mutants. Brain Res 374:260–269. doi: 10.1016/0006-8993(86)90420-8 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Thomas N. Seyfried
    • 1
    Email author
  • Karie A. Heinecke
    • 1
  • John G. Mantis
    • 1
  • Christine A. Denny
    • 1
    • 2
  1. 1.Department of BiologyBoston CollegeBostonUSA
  2. 2.Department of Biological SciencesColumbia UniversityColumbiaUSA

Personalised recommendations