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:

SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects

Molecular Psychiatry volume 13, pages 385–397 (2008)Cite this article

Abstract

Autism is a neurodevelopmental disorder with a strong genetic component, probably involving several genes. Genome screens have provided evidence of linkage to chromosome 2q31–q33, which includes the SLC25A12 gene. Association between autism and single-nucleotide polymorphisms in SLC25A12 has been reported in various studies. SLC25A12 encodes the mitochondrial aspartate/glutamate carrier functionally important in neurons with high-metabolic activity. Neuropathological findings and functional abnormalities in autism have been reported for Brodmann's area (BA) 46 and the cerebellum. We found that SLC25A12 was expressed more strongly in the post-mortem brain tissues of autistic subjects than in those of controls, in the BA46 prefrontal cortex but not in cerebellar granule cells. SLC25A12 expression was not modified in brain subregions of bipolar and schizophrenic patients. SLC25A12 was expressed in developing human neuronal tissues, including neocortical regions containing excitatory neurons and neocortical progenitors and the ganglionic eminences that generate neocortical inhibitory interneurons. At mid-gestation, when gyri and sulci start to develop, SLC25A12 molecular gradients were identified in the lateral prefrontal and ventral temporal cortex. These fetal structures generate regions with abnormal activity in autism, including the dorsolateral prefrontal cortex (BA46), the pars opercularis of the inferior frontal cortex and the fusiform gyrus. SLC25A12 overexpression or silencing in mouse embryonic cortical neurons also modified dendrite length and the mobility of dendritic mitochondria. Our findings suggest that SLC25A12 overexpression may be involved in the pathophysiology of autism, modifying neuronal networks in specific subregions, such as the dorsolateral prefrontal cortex and fusiform gyrus, at both pre- and postnatal stages.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Kanner L . Autistic disturbances of affective contact. Nerv Child 1943; 2: 217–250.

    Google Scholar 

  2. Volkmar FR, Pauls D . Autism. Lancet 2003; 362: 1133–1141.

    PubMed  Google Scholar 

  3. Tuchman R, Rapin I . Epilepsy in autism. Lancet Neurol 2002; 1: 352–358.

    Article  Google Scholar 

  4. Veenstra-VanderWeele J, Cook Jr EH . Molecular genetics of autism spectrum disorder. Mol Psychiatry 2004; 9: 819–832.

    Article  CAS  Google Scholar 

  5. Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL et al. Related linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 2004; 161: 662–669.

    Article  Google Scholar 

  6. Blasi F, Bacchelli E, Carone S, Toma C, Monaco AP, Bailey AJ, et al., International Molecular Genetic Study of Autism Consortium (IMGSAC). SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample. Eur J Hum Genet 2006; 14: 123–126.

    Article  CAS  Google Scholar 

  7. Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L . Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31. Am J Psychiatry 2005; 162: 2182–2184.

    Article  Google Scholar 

  8. Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS et al. Lack of association between autism and SLC25A12. Am J Psychiatry 2006; 163: 929–931.

    Article  Google Scholar 

  9. Turunen J, Tero Ylisaukko-oja T, Kilpine H, Rehnström K, Kempas E, Vanhala R et al. Association Analysis of SLC25A12 and EN2 in the Finnish Families with Autism-Spectrum Disorders. WCPG: Cagliari, Italy, 2006, abstracts.

    Google Scholar 

  10. del Arco A, Satrustegui J . Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain. J Biol Chem 1998; 273: 23327–23334.

    Article  CAS  Google Scholar 

  11. Attwell D, Laughlin SB . An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 2001; 21: 1133–1145.

    Article  CAS  Google Scholar 

  12. Elston GN . Pyramidal cells of the frontal lobe: all the more spinous to think with. J Neurosci 2000; 20: RC95.

    Article  CAS  Google Scholar 

  13. Elston GN . Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function. Cereb Cortex 2003; 13: 1124–1138.

    Article  Google Scholar 

  14. Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI et al. Evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA 2006; 103: 13606–13611.

    Article  CAS  Google Scholar 

  15. Bauman ML, Kemper TL . Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci 2005; 23: 183–187.

    Article  Google Scholar 

  16. Palmen SJ, van Engeland H, Hof PR, Schmitz C . Neuropathological findings in autism. Brain 2004; 127: 2572–2583.

    Article  Google Scholar 

  17. Baron-Cohen S, Belmonte MK . Autism: a window onto the development of the social and the analytic brain. Annu Rev Neurosci 2005; 28: 109–126.

    Article  CAS  Google Scholar 

  18. DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C et al. The developmental neurobiology of autism spectrum disorder. J Neurosci 2006; 26: 6897–6906.

    Article  CAS  Google Scholar 

  19. Letinic K, Zoncu R, Rakic P . Origin of GABAergic neurons in the human neocortex. Nature 2002; 417: 645–649.

    Article  CAS  Google Scholar 

  20. Rakic P . Specification of cerebral cortical areas. Science 1988; 241: 170–176.

    Article  CAS  Google Scholar 

  21. Whitford KL, Dijkhuizen P, Polleux F, Ghosh A . Molecular control of cortical dendrite development. Annu Rev Neurosci 2002; 25: 127–149.

    Article  CAS  Google Scholar 

  22. Li Z, Okamoto K, Hayashi Y, Sheng M . The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 2004; 119: 873–887.

    Article  CAS  Google Scholar 

  23. Ohnishi T, Yamada K, Ohba H, Iwayama Y, Toyota T, Hattori E et al. A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology 2007; 32: 1727–1737.

    Article  CAS  Google Scholar 

  24. Aoki-Suzuki M, Yamada K, Meerabux J, Iwayama-Shigeno Y, Ohba H, Iwamoto K et al. A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia. Biol Psychiatry 2005; 57: 382–393.

    Article  CAS  Google Scholar 

  25. Nakatani N, Hattori E, Ohnishi T, Dean B, Iwayama Y, Matsumoto I et al. Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation. Hum Mol Genet 2006; 15: 1949–1962.

    Article  CAS  Google Scholar 

  26. Al Halabiah H, Delezoide AL, Cardona A, Moalic JM, Simonneau M . Expression pattern of NOGO and NgR genes during human development. Gene Expr Patterns 2005; 5: 561–568.

    Article  CAS  Google Scholar 

  27. Charpak G, Dominik W, Zaganidis N . Optical imaging of the spatial distribution of beta-particles emerging from surfaces. Proc Natl Acad Sci USA 1989; 86: 1741–1745.

    Article  CAS  Google Scholar 

  28. Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 2006; 124: 1283–1298.

    Article  CAS  Google Scholar 

  29. Amano T, Richelson E, Nirenberg M . Neurotransmitter synthesis by neuroblastoma clones (neuroblast differentiation-cell culture-choline acetyltransferase-acetylcholinesterase-tyrosine hydroxylase-axons-dendrites). Proc Natl Acad Sci USA 1972; 69: 258–263.

    Article  CAS  Google Scholar 

  30. Stoppini L, Buchs PA, Muller D . A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 199; 37: 173–182.

    Article  Google Scholar 

  31. Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S . Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 2004; 61: 300–308.

    Article  CAS  Google Scholar 

  32. Iwamoto K, Bundo M, Kato T . Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet 2005; 14: 241–253.

    Article  CAS  Google Scholar 

  33. Sultana R, Yu CE, Yu J, Munson J, Chen D, Hua W et al. Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 2002; 80: 129–134.

    Article  CAS  Google Scholar 

  34. Richler E, Reichert JG, Buxbaum JD, McInnes LA . Autism and ultraconserved non-coding sequence on chromosome 7q. Psychiatr Genet 2006; 16: 19–23.

    Article  Google Scholar 

  35. Philippi A, Roschmann E, Tores F, Lindenbaum P, Benajou A, Germain-Leclerc L et al. Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism. Mol Psychiatry 2005; 10: 950–960.

    Article  CAS  Google Scholar 

  36. Hirono M, Sugiyama T, Kishimoto Y, Sakai I, Miyazawa T, Kishio M et al. Phospholipase Cbeta4 and protein kinase Calpha and/or protein kinase CbetaI are involved in the induction of long term depression in cerebellar Purkinje cells. J Biol Chem 2001; 276: 45236–45242.

    Article  CAS  Google Scholar 

  37. Kaufman M . Mouse and human embryonic development: a comparative overview. In: Strachan T, Lindsay S, Wilson DI (eds). Molecular Genetics of Early Human Development. T. BIOS Scientific Publishers Ltd.: Oxford, UK, 1997, pp 77–110.

    Google Scholar 

  38. Rakic P, Nowakowski RS . The time of origin of neurons in the hippocampal region of the rhesus monkey. J Comp Neurol 1981; 196: 99–128.

    Article  CAS  Google Scholar 

  39. Nowakowski RS, Rakic P . The site of origin and route and rate of migration of neurons to the hippocampal region of the rhesus monkey. J Comp Neurol 1981; 196: 129–154.

    Article  CAS  Google Scholar 

  40. Khazipov R, Esclapez M, Caillard O, Bernard C, Khalilov I, Tyzio R et al. Early development of neuronal activity in the primate hippocampus in utero. J Neurosci 2001; 21: 9770–9781.

    Article  CAS  Google Scholar 

  41. Whitford KL, Marillat V, Stein E, Goodman CS, Tessier-Lavigne M, Chedotal A et al. Regulation of cortical dendrite development by Slit–Robo interactions. Neuron 2002; 33: 47–61.

    Article  CAS  Google Scholar 

  42. Li Z, Okamoto K, Hayashi Y, Sheng M . The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 2004; 119: 873–887.

    Article  CAS  Google Scholar 

  43. Carper RA, Courchesne E . Localized enlargement of the frontal cortex in early autism. Biol Psychiatry 2005; 57: 126–133.

    Article  Google Scholar 

  44. Casanova MF, Buxhoeveden DP, Switala AE, Roy E . Minicolumnar pathology in autism. Neurology 2002; 58: 428–432.

    Article  Google Scholar 

  45. Luna B, Minshew NJ, Garver KE, Lazar NA, Thulborn KR, Eddy WF et al. Neocortical system abnormalities in autism: an fMRI study of spatial working memory. Neurology 2002; 59: 834–840.

    Article  CAS  Google Scholar 

  46. Silk TJ, Rinehart N, Bradshaw JL, Tonge B, Egan G, O'Boyle MW et al. Related articles, links visuospatial processing and the function of prefrontal-parietal networks in autism spectrum disorders: a functional MRI study. Am J Psychiatry 2006; 163: 1440–1443.

    Article  Google Scholar 

  47. McAlonan GM, Cheung V, Cheung C, Suckling J, Lam GY, Tai KS et al. Mapping the brain in autism. A voxel-based MRI study of volumetric differences and intercorrelations in autism. Brain 2005; 128: 268–276.

    Article  Google Scholar 

  48. Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ . Autism and abnormal development of brain connectivity. J Neurosci 2004; 24: 9228–9231.

    Article  CAS  Google Scholar 

  49. Ramos M, del Arco A, Pardo B, Martinez-Serrano A, Martinez-Morales JR, Kobayashi K et al. Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Brain Res Dev Brain Res 2003; 143: 33–46.

    Article  CAS  Google Scholar 

  50. Fougerousse F, Bullen P, Herasse M, Lindsay S, Richard I, Wilson D et al. Human-mouse differences in the embryonic expression patterns of developmental control genes and disease genes. Hum Mol Genet 2000; 9: 165–173.

    Article  CAS  Google Scholar 

  51. Donoghue MJ, Rakic P . Molecular gradients and compartments in the embryonic primate cerebral cortex. Cereb Cortex 1999; 9: 586–600.

    Article  CAS  Google Scholar 

  52. Sur M, Rubenstein JL . Patterning and plasticity of the cerebral cortex. Science 2005; 310: 805–810.

    Article  CAS  Google Scholar 

  53. Rizzolatti G, Craighero L . The mirror-neuron system. Annu Rev Neurosci 2004; 27: 169–192.

    Article  CAS  Google Scholar 

  54. Dapretto M, Davies MS, Pfeifer JH, Scott AA, Sigman M, Bookheimer SY et al. Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Nat Neurosci 2006; 9: 28–30.

    Article  CAS  Google Scholar 

  55. Pierce K, Haist F, Sedaghat F, Courchesne E . The brain response to personally familiar faces in autism: findings of fusiform activity and beyond. Brain 2004; 127: 2703–2716.

    Article  Google Scholar 

  56. Dalton KM, Nacewicz BM, Johnstone T, Schaefer HS, Gernsbacher MA, Goldsmith HH et al. Gaze fixation and the neural circuitry of face processing in autism. Nat Neurosci 2005; 8: 519–526.

    Article  CAS  Google Scholar 

  57. Dent EW, Gertler FB . Cytoskeletal dynamics and transport in growth cone motility and axon guidance. Neuron 2003; 40: 209–227.

    Article  CAS  Google Scholar 

  58. Hirokawa N, Takemura R . Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 2005; 6: 201–214.

    Article  CAS  Google Scholar 

  59. Lasorsa FM, Pinton P, Palmieri L, Fiermonte G, Rizzuto R, Palmieri F . Recombinant expression of the Ca(2+)-sensitive aspartate/glutamate carrier increases mitochondrial ATP production in agonist-stimulated Chinese hamster ovary cells. J Biol Chem 2003; 278: 38686–38692.

    Article  CAS  Google Scholar 

  60. Pardo B, Contreras L, Serrano A, Ramos M, Kobayashi K, Iijima M et al. Essential role of aralar in the transduction of small Ca2+ signals to neuronal mitochondria. J Biol Chem 2006; 281: 1039–1047.

    Article  CAS  Google Scholar 

  61. Geschwind DH, Levitt P . Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 2007; 17: 103–111.

    Article  CAS  Google Scholar 

  62. Hemann MT, Fridman JS, Zilfou JT, Hernando E, Paddison PJ, Cordon-Cardo C et al. An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nat Genet 2003; 33: 396–400.

    Article  CAS  Google Scholar 

  63. Mager J, Bartolomei MS . Strategies for dissecting epigenetic mechanisms in the mouse. Nat Genet 2005; 37: 1194–1200.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by INSERM, Fondation France-Télécom and Fédération pour la Recherche sur le Cerveau. AMLB received a fellowship from Fondation des Treilles. We thank Dr Jane Pickett at the Autism Tissue Program for facilitating tissue collection. Tissue samples were provided by the National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Miami, from Director Dr Carol Petito; the Harvard Brain Tissue Resource Center, from Director Dr Francine Benes. Bipolar and schizophrenia tissue samples were donated by the Stanley Foundation (Bethedsa, MD, USA). We thank Dr Manuel Rojo, INSERM U582, for providing the DsRedMito plasmid and advice, and Christophe Chamot and Tristan Piolot, Imagerie, Institut Jacques Monod for assistance with videomicroscopy analysis.

Author information

Authors and Affiliations

  1. INSERM U675, IFR2, Faculté de Médecine Xavier Bichat, Paris, France

    A-M Lepagnol-Bestel, G Maussion, J-M Moalic, P Gorwood, N Ramoz & M Simonneau

  2. Department of Basic Neuroscience, Centre Medical Universitaire, Geneva, Switzerland

    B Boda & D Muller

  3. Histotechnology and Pathology Unit, Institut Pasteur, Paris, France

    A Cardona

  4. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan

    Y Iwayama & T Yoshikawa

  5. Biologie du développement, Hôpital Robert Debré, AP-HP, Paris, France

    A-L Delezoide

  6. The Rebecca L Cooper Research Laboratories, Mental Health Research Institute of Victoria, Parkville, VIC, Australia

    B Dean

  7. CREST, Japan Science and Technology Agency, Saitama, Japan

    T Yoshikawa

  8. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

    J D Buxbaum

  9. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    J D Buxbaum

Authors
  1. A-M Lepagnol-Bestel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Maussion
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Boda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Cardona
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Iwayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A-L Delezoide
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J-M Moalic
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. B Dean
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P Gorwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J D Buxbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. N Ramoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Simonneau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Simonneau.

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

Lepagnol-Bestel, AM., Maussion, G., Boda, B. et al. SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Mol Psychiatry 13, 385–397 (2008). https://doi.org/10.1038/sj.mp.4002120

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4002120

Keywords

This article is cited by

Search

Advanced search

Quick links