Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders

Abstract

Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 667–675.

    Article  CAS  Google Scholar 

  2. Kolevzon A, Gross R, Reichenberg A . Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 2007; 161: 326–333.

    Article  Google Scholar 

  3. Limperopoulos C, Bassan H, Sullivan NR, Soul JS, Robertson Jr RL, Moore M et al. Positive screening for autism in ex-preterm infants: prevalence and risk factors. Pediatrics 2008; 121: 758–765.

    Article  Google Scholar 

  4. Toal F, Murphy DG, Murphy KC . Autistic-spectrum disorders: lesson from neuroimaging. Br J Psychiatry 2005; 187: 395–397.

    Article  Google Scholar 

  5. Haznedar MM, Buchsbaum MS, Wei TC, Hof PR, Cartwright C, Bienstock CA et al. Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 2000; 157: 1994–2001.

    Article  CAS  Google Scholar 

  6. Haznedar MM, Buchsbaum MS, Hazlett EA, LiCalzi EM, Cartwright C, Hollander E . Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders. Am J Psychiatry 2006; 163: 1252–1263.

    Article  Google Scholar 

  7. Simpson IA, Carruthers A, Vannucci SJ . Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 2007; 27: 1766–1791.

    Article  CAS  Google Scholar 

  8. Devaskar S, Zahm DS, Holtzclaw L, Chundu K, Wadzinski BE . Developmental regulation of the distribution of rat brain insulin-insensitive (Glut 1) glucose transporter. Endocrinology 1991; 129: 1530–1540.

    Article  CAS  Google Scholar 

  9. Mantych GJ, James DE, Chung HD, Devaskar SU . Cellular localization and characterization of Glut 3 glucose transporter isoform in human brain. Endocrinology 1992; 131: 1270–1278.

    Article  CAS  Google Scholar 

  10. Sankar R, Thamotharan S, Shin D, Moley KH, Devaskar SU . Insulin-responsive glucose transporters-GLUT8 and GLUT4 are expressed in the developing brain. Brain Res Mol Brain Res 2002; 107: 157–165.

    Article  CAS  Google Scholar 

  11. Shin BC, McKnight RA, Devaskar SU . Glucose transporter GLUT8 translocation in neurons is not insulin responsive. J Neurosci Res 2004; 75: 835–844.

    Article  CAS  Google Scholar 

  12. Maher F, Davies-Hill TM, Simpson IA . Substrate specificity and kinetic parameters of GLUT3 in rat cerebellar granule neurons. Biochem J 1995; 315 (Part 3): 827–831.

    Google Scholar 

  13. Ganguly A, McKnight RA, Raychaudhuri S, Shin BC, Ma Z, Moley K et al. Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction. Am J Physiol Endocrinol Metab 2007; 292: E1241–E1255.

    Article  CAS  Google Scholar 

  14. Khan JY, Rajakumar RA, McKnight RA, Devaskar UP, Devaskar SU . Developmental regulation of genes mediating murine brain glucose uptake. Am J Physiol 1999; 276: R892–R900.

    Article  CAS  Google Scholar 

  15. Rajakumar A, Thamotharan S, Raychaudhuri N, Menon RK, Devaskar SU . Trans-activators regulating neuronal glucose transporter isoform-3 gene expression in mammalian neurons. J Biol Chem 2004; 279: 26768–26779.

    Article  CAS  Google Scholar 

  16. Ito K, Sawada Y, Ishizuka H, Sugiyama Y, Suzuki H, Iga T et al. Measurement of cerebral glucose-utilization from brain uptake of {C-14} 2-deoxyglucose and {H-3} 3-O-methylglucose in the mouse. J Pharmacol Methods 1990; 23: 129–140.

    Article  CAS  Google Scholar 

  17. Zovein A, Flowers-Ziegler J, Thamotharan S, Shin D, Sankar R, Nguyen K et al. Postnatal hypoxic-ischemic brain injury alters mechanisms mediating neuronal glucose transport. Am J Physiol Regul Integr Comp Physiol 2004; 286: R273–R282.

    Article  CAS  Google Scholar 

  18. Oldendorf WH . Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res 1970; 24: 372–376.

    Article  CAS  Google Scholar 

  19. Choeiri C, Staines WA, Miki T, Seino S, Renaud JM, Teutenberg K et al. Cerebral glucose transporters expression and spatial learning in the K-ATP Kir6.2(−/−) knockout mice. Behav Brain Res 2006; 172: 233–239.

    Article  CAS  Google Scholar 

  20. Thamotharan M, Shin BC, Suddirikku DT, Thamotharan S, Garg M, Devaskar SU . GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring. Am J Physiol Endocrinol Metab 2005; 288: E935–E947.

    Article  CAS  Google Scholar 

  21. Dube C, Richichi C, Bender RA, Chung G, Litt B, Baram TZ . Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis. Brain 2006; 129: 911–922.

    Article  Google Scholar 

  22. Irwin S . Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia 1968; 13: 222–257.

    Article  CAS  Google Scholar 

  23. Rafael JA, Nitta Y, Peters J, Davies KE . Testing of SHIRPA, a mouse phenotypic assessment protocol, on Dmd(mdx) and Dmd(mdx3cv) dystrophin-deficient mice. Mamm Genome 2000; 11: 725–728.

    Article  CAS  Google Scholar 

  24. Lawhorn C, Smith DM, Brown LL . Striosome-matrix pathology and motor deficits in the YAC128 mouse model of Huntington's disease. Neurobiol Dis 2008; 32: 471–478.

    Article  CAS  Google Scholar 

  25. Avale ME, Falzone TL, Gelman DM, Low MJ, Grandy DK, Rubinstein M . The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. Mol Psychiatry 2004; 9: 718–726.

    Article  CAS  Google Scholar 

  26. Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 2004; 3: 287–302.

    Article  CAS  Google Scholar 

  27. Scattoni ML, Gandhy SU, Ricceri L, Crawley JN . Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism. PLoS ONE 2008; 3: e3067.

    Article  Google Scholar 

  28. Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 2007; 176: 4–20.

    Article  Google Scholar 

  29. McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN . Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav 2008; 7: 152–163.

    Article  CAS  Google Scholar 

  30. Kelley AE . Measurement of rodent stereotyped behavior. Curr Protoc Neurosci 1998; pp 8.8.1–8.8.6, Wiley, New York, USA.

    Google Scholar 

  31. Morris R . Development of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11: 47–60.

    Article  CAS  Google Scholar 

  32. Nakajo Y, Miyamoto S, Nakano Y, Xue JH, Hori T, Yanamoto H . Genetic increase in brain-derived neurotrophic factor levels enhances learning and memory. Brain Res 2008; 1241: 103–109.

    Article  CAS  Google Scholar 

  33. Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A et al. Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol Psychiatry 2003; 8: 217–224.

    Article  CAS  Google Scholar 

  34. Blaeser F, Sanders MJ, Truong N, Ko S, Wu LJ, Wozniak DF et al. Long-term memory deficits in Pavlovian fear conditioning in Ca2+/calmodulin kinase kinase alpha-deficient mice. Mol Cell Biol 2006; 26: 9105–9115.

    Article  CAS  Google Scholar 

  35. Pierre K, Pellerin L . Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 2005; 94: 1–14.

    Article  CAS  Google Scholar 

  36. D'Ambrosio R, Fender JS, Fairbanks JP, Simon EA, Born DE, Doyle DL et al. Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat. Brain 2005; 128: 174–188.

    Article  Google Scholar 

  37. Wolfer DP, Stagljar-Bozicevic M, Errington ML, Lipp HP . Spatial memory and learning in transgenic mice: fact or artifact? News Physiol Sci 1998; 13: 118–123.

    Google Scholar 

  38. Matus-Amat P, Higgins EA, Barrientos RM, Rudy JW . The role of the dorsal hippocampus in the acquisition and retrieval of context memory representations. J Neurosci 2004; 24: 2431–2439.

    Article  CAS  Google Scholar 

  39. Yu S, Zhao T, Guo M, Fang H, Ma J, Ding A et al. Hypoxic preconditioning up-regulates glucose transport activity and glucose transporter (GLUT1 and GLUT3) gene expression after acute anoxic exposure in the cultured rat hippocampal neurons and astrocytes. Brain Res 2008; 1211: 22–29.

    Article  CAS  Google Scholar 

  40. Bruckner BA, Ammini CV, Otal MP, Raizada MK, Stacpoole PW . Regulation of brain glucose transporters by glucose and oxygen deprivation. Metabolism 1999; 48: 422–431.

    Article  CAS  Google Scholar 

  41. Sadiq F, Holtzclaw L, Chundu K, Muzzafar A, Devaskar S . The ontogeny of the rabbit brain glucose transporters. Endocrinology 1990; 126: 2417–2424.

    Article  CAS  Google Scholar 

  42. Schmidt S, Richter M, Montag D, Sartorius T, Gawlik V, Hennige AM et al. Neuronal functions, feeding behavior, and energy balance in Slc2a3+/− mice. Am J Physiol Endocrinol Metab 2008; 295: E1084–E1094.

    Article  CAS  Google Scholar 

  43. Pellerin L . How astrocytes feed hungry neurons. Mol Neurobiol 2005; 32: 59–72.

    Article  CAS  Google Scholar 

  44. Heilig CW, Saunders T, Brosius III FC, Moley K, Heilig K, Baggs R et al. Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy. Proc Natl Acad Sci USA 2003; 100: 15613–15618.

    Article  CAS  Google Scholar 

  45. Jensen PJ, Gitlin JD, Carayannopoulos MO . GLUT1 deficiency links nutrient availability and apoptosis during embryonic development. J Biol Chem 2006; 281: 13382–13387.

    Article  CAS  Google Scholar 

  46. Wang D, Pascual JM, Yang H, Engelstad K, Mao X, Cheng J et al. A mouse model for Glut-1 haploinsufficiency. Hum Mol Genet 2006; 15: 1169–1179.

    Article  CAS  Google Scholar 

  47. De Vivo DC, Trifiletti R, Jacobson RI, Ronen GM, Behmand RA, Harik SI . GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. New Engl J Med 1991; 325: 703–709.

    Article  CAS  Google Scholar 

  48. Seidner G, Alvarez MG, Yeh J-I, Driscoll KR, Klepper J, Stump TS et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 1998; 18: 188–191.

    Article  CAS  Google Scholar 

  49. Klepper J, Wang D, Fischbarg J, Vera JC, Jarjour IT, O'Driscoll KR et al. Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome. Neurochem Res 1998; 24: 587–594.

    Article  Google Scholar 

  50. Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP et al. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 2005; 57: 111–118.

    Article  CAS  Google Scholar 

  51. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ . Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 1995; 377: 151–155.

    Article  CAS  Google Scholar 

  52. Kotani K, Peroni OD, Minokoshi Y, Boss O, Kahn BB . GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. J Clin Invest 2004; 114: 1666–1675.

    Article  CAS  Google Scholar 

  53. Membrez M, Hummler E, Beermann F, Haefliger JA, Savioz R, Pedrazzini T et al. GLUT8 is dispensable for embryonic development but influences hippocampal neurogenesis and heart function. Mol Cell Biol 2006; 26: 4268–4276.

    Article  CAS  Google Scholar 

  54. Schmidt S, Gawlik V, Holter SM, Augustin R, Scheepers A, Behrens M et al. Deletion of glucose transporter GLUT8 in mice increases locomotor activity. Behav Genet 2008; 38: 396–406.

    Article  CAS  Google Scholar 

  55. Myers SM, Johnson CP . Management of children with autism spectrum disorders. Pediatrics 2008; 120: 1162–1182.

    Article  Google Scholar 

  56. Scattoni ML, Crawley J, Ricceri L . Ultrasonic vocalizations: a tool for behavioral phenotyping of mouse models of neurodevelopmental disorders. Neurosci Behav Rev 2009; 33: 508–515.

    Article  Google Scholar 

  57. Dirks A, Fish EW, Kikusui T, van der Gugten J, Groenink L, Olivier B et al. Effects of corticotropin-releasing hormone on distress vocalizations and locomotion in maternally separated mouse pups. Pharmacol Biochem Behav 2002; 72: 993–999.

    Article  CAS  Google Scholar 

  58. Ganguly A, Devaskar SU . Glucose transporter-3 null heterozygous mutation causes sexually dimorphic adiposity with insulin resistance. Am J Physiol Endocrinol Metab 2008; 294: E1144–E1151.

    Article  CAS  Google Scholar 

  59. Chadman KK, Gong S, Scattoni ML, Boltuck SE, Gandhy SU, Heintz N et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res 2008; 1: 147–158.

    Article  Google Scholar 

  60. Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F et al. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci USA 2008; 105: 1710–1715.

    Article  CAS  Google Scholar 

  61. Sheinkopf SJ, Mundy P, Oiler DK, Steffens M . Vocal atypicalities of preverbal autistic children. Autism Dev Disord 2000; 30: 345–354.

    Article  CAS  Google Scholar 

  62. Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 2007; 318: 71–76.

    Article  CAS  Google Scholar 

  63. Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M, Gottmann L et al. Neuroligins determine synapse maturation and function. Neuron 2006; 51: 741–754.

    Article  CAS  Google Scholar 

  64. De Jaco A, Comoletti D, King CC, Taylor P . Trafficking of cholinesterases and neuroligins mutant proteins: an association with autism. Chem Biol Interact 2006; 175: 349–351.

    Article  Google Scholar 

  65. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008; 321: 218–223.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NIH HD33997 and HD46979 (SUD), whereas the EEG studies were partly supported by NS 046516 (RS). Camille Fung was supported by an NIH T32 HD07549 training grant. We thank Lynn Talton in the UCLA Behavioral Testing Core Laboratory, Brian Wiltgen and Brett Abrahams for their guidance with certain neurobehavioral studies.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S U Devaskar.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, Y., Fung, C., Shin, D. et al. Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders. Mol Psychiatry 15, 286–299 (2010). https://doi.org/10.1038/mp.2009.51

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2009.51

Keywords

This article is cited by

Search

Quick links