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Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications

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Abstract

The recent identification of decreased protein levels of glutamate decarboxylase (GAD) 65 and 67 isoforms in the autistic cerebellar tissue raises the possibility that abnormal regulation of GABA production in individual neurons may contribute to the clinical features of autism. Reductions in Purkinje cell number have been widely reported in autism. It is not known whether the GAD changes also occur in Purkinje cells at the level of transcription. Using a novel approach, the present study quantified GAD67 mRNA, the most abundant isoform in Purkinje cells, using in situ hybridization in adult autistic and control cases. The results indicate that GAD67 mRNA level was reduced by 40% in the autistic group (P < 0.0001; two-tailed t test), suggesting that reduced Purkinje cell GABA input to the cerebellar nuclei potentially disrupts cerebellar output to higher association cortices affecting motor and/or cognitive function. These findings may also contribute to the understanding of previous reports of alterations in the GABAergic system in limbic and cerebro-cortical areas contributing to a more widespread pathophysiology in autistic brains.

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References

  1. Aggensteiner M, Reiser G (2003) Expression of the brain-specific membrane adapter protein p42IP4/centaurin alpha, a Ins(1,3,4,5)P4/PtdIns(3,4,5)P3 binding protein, in developing rat brain. Dev Brain Res 142:77–87

    Article  CAS  Google Scholar 

  2. Arin DM, Bauman ML, Kemper TL (1991) The distribution of Purkinje cell loss in the cerebellum in autism. Neurology 41(Suppl):307

    Google Scholar 

  3. Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K (1997) Cleft palate and decrased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 94(12): 6496–6499

    Article  PubMed  CAS  Google Scholar 

  4. Bauman ML, Kemper TL (1985) Histoanatomic observations of the brain in early infantile autism. Neurology 35:866–874

    PubMed  CAS  Google Scholar 

  5. Bauman ML, Kemper TL (1994) Neuroanatomic observations of the brain in autism. In: Bauman ML, Kemper TL (eds) The neurobiology of autism. John Hopkins University Press, Baltimore, pp 119–145

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  7. Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML (2001) Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord 31(6):537–543

    Article  PubMed  CAS  Google Scholar 

  8. Blatt GJ (2005) GABAergic cerebellar system in autism: a neuropathological and developmental perspective. Int Rev Neurobiol 71:167–178

    PubMed  CAS  Google Scholar 

  9. Brooksbank BW, Atkinson DJ, Balazs R (1981) Biochemical development of the human brain. II. Some parameters of the GABAergic system. Dev Neurosci 4(3):188–200

    PubMed  CAS  Google Scholar 

  10. Bu DF, Erlander MG, Hiltz BC, Tillakaratne NJK, Kaufman DI, Wagber-McPherson CB, Evan GA, Tobin AJ (1992) Two human glutamate decarboxylase, 65 kDa GAD and 67 kDa GAD, are each encoded by a single gene. Proc Natl Acad Sci USA 89:2115–2119

    Article  PubMed  CAS  Google Scholar 

  11. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E, Lawlor BA, Fitzgerald M, Greenberg DA, Davis KL (2001) Evidence for a susceptibility gene for autism chromosome 2 for genetic heterogeneity. Am J Hum Genet 68(6):1514–1520

    Article  PubMed  CAS  Google Scholar 

  12. Center for Disease Control (CDC): 2006 autismspeaks.org

  13. Chan-Palay V, Palay SL, Wu JY (1979) Gamma-aminobutyric acid pathways in the cerebellum studied by retrograde and anterograde transport of glutamic acid decarboxylase antibody after in vivo injections. Anat Embryol (Berl) 157(1):1–14

    Article  CAS  Google Scholar 

  14. Chesselet MF, Weiss L, Wuenschell C, Tobin AJ, Affolter H-U (1987) Comparative distribution of mRNAs for glutamic acid decarboxylase, tyrosine hydroxylase, and tachykinins in the basal ganglia: an in situ hybridization study in the rodent brain. J Comp Neurol 262:125–140

    Article  PubMed  CAS  Google Scholar 

  15. Cox KH, DeLeon DV, Angerer LM, Angerer RC (1984) Detection of mRNAs in sea urchin embryos by in situ hybridization using asymmetric RNA probes. Dev Biol 101:485–502

    Article  PubMed  CAS  Google Scholar 

  16. Crepel F, Mariani J (1976) Multiple innervation of Purkinje cells by climbing fibers in the cerebellum of the weaver mutant mouse. J Neurobiol 7(6):579–582

    Article  PubMed  CAS  Google Scholar 

  17. Crepel F, Delhaye-Bouchaud N, Guastavino JM, Sampaio I (1980) Multiple innervation of cerebellar Purkinje cells by climbing fibers in staggerer mutant mouse. Nature 283(5746):483–484

    Article  PubMed  CAS  Google Scholar 

  18. Dhossche D, Applegate H, Abraham A, Maertens P, Bland L, Bencsath A, Martinez J (2002) Elevated plasma GABA levels in autistic youngsters: stimulus for a GABA hypothesis in autism. Med Sci Monitor 8(8):PR1–PR6

    CAS  Google Scholar 

  19. Drengler SM, Oltman GA (1993) Rapid increases in cerebellar Purkinje cell glutamic acid decarboxylase GAD67 mRNA after lesion-induced increases in cell firing. Brain Res 615(1):175–179

    Article  PubMed  CAS  Google Scholar 

  20. Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (1991a) Two genes encode distinct glutamate decarboxylases. Neuron 7:91–100

    Article  CAS  Google Scholar 

  21. Erlander MG, Tobin AJ (1991b) The structural and functional heterogeneity of glutamate decarboxylase. A review. Neurochem Res 16:215–226

    Article  CAS  Google Scholar 

  22. Esclapez M, Tillakaratne NJK, Tobin AJ, Houser CR (1993) Comparative localization of mRNAs encoding two forms of glutamic acid decarboxylase with non radioactive in situ hybridization methods. J Comp Neurol 331:339–362

    Article  PubMed  CAS  Google Scholar 

  23. Esclapez M, Tillakaratne NJ, Kaufman DL, Tobin AJ, Houser CR (1994) Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci 14(3 Pt 2):1834–1855

    PubMed  CAS  Google Scholar 

  24. Fatemi SH, Halt AR, Realmuto G, Earle J, Kist DA, Thuras P, Mer A (2002a) Purkinje cell size is reduced in cerebellum of patients with autism. Cell Mol Neurobiol 22(2):171–175

    Article  Google Scholar 

  25. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR (2002b) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psych 52:805–810

    Article  CAS  Google Scholar 

  26. Feldblum S, Erlander MG, Tobin AJ (1993) Different distributions of GAD65 and GAD67 mRNAs suggest that the two glutamate decarboxylases play distinctive functional roles. J Neurosci Res 34(6):689–706

    Article  PubMed  CAS  Google Scholar 

  27. Greger V, Knoll JH, Woolf F, Glatt K, Tyndale RF, DeLorey TM, Olsen RW, Tobin AJ, Sikela JM, Nakatsu Y et al (1995) The gamma-aminobutyric acid receptor gamma 3 subunit gene (GABARG3) is tightly linked to the alpha 5 subunit gene (GABRA5) on human chromosome 15q11-q13 and is transcribed in the same orientation. Genomics 26(2):258–264

    Article  PubMed  CAS  Google Scholar 

  28. Gepner B, Mestre DR (2002) Postural reactivity to fast visual motion differentiates autistic from children with Asperger syndrome. J Autism Dev Disord 32:231–238

    Article  PubMed  Google Scholar 

  29. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevinin V, Dwivedi Y, Grayson DR, Impagnateillo F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E (2000) Decrease in reelin and glutamic acid decarboxylase 67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 57(11):1061–1069

    Article  PubMed  CAS  Google Scholar 

  30. Hamilton SP, Woo JM, Carlson EJ, Ghanem E, Ekker M, Rubenstein JLR (2005) Analysis of four DLX homeobox genes in autistic probands. BMC Genetics 6:52

    Article  PubMed  CAS  Google Scholar 

  31. Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA (2005) Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 25(2):372–383

    Article  PubMed  CAS  Google Scholar 

  32. Heckers S, stone D, Walsh J, Shick J, Koul P, Benes FM (2002) Differential hippocampal expression glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psych 59(6):521–529

    Article  CAS  Google Scholar 

  33. Hynd M, Lewohl JM, Scott HL, Dodd PR (2003) Biochemical and molecular studies using human autopsy brain tissue. J Neurochem 85:543–562

    Article  PubMed  CAS  Google Scholar 

  34. IMGSAC (2001) A genomewide screen for autism: strong evidence for linkage to chromosome 2q, 7q, and 16p. Am J Hum Genet 69:570–581

    Google Scholar 

  35. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA 95(26):15718–15723

    Article  PubMed  CAS  Google Scholar 

  36. Jeneskog T, Padel Y (1984) An excitatory pathway through dorsal columns to rubrospinal cells in the cat. J Physiol 353:355–373

    PubMed  CAS  Google Scholar 

  37. Jones RS (1988) Epileptiform events induced by GABA-antagonists in entorhinal cortical cells in vitro are partly mediated by NMDA receptors. Brain Res 457(1):113–121

    Article  PubMed  CAS  Google Scholar 

  38. Jones MW, Kilpatrick IC, Phillipson OT (1988) Dopamine function in the prefrontal cortex of the rat is sensitive to a reduction of tonic GABA-mediated inhibition in the thalamic mediodorsal nucleus. Exp Brain Res 69(3):623–634

    Article  PubMed  CAS  Google Scholar 

  39. Kalkman HO, Loetscher (2003) GAD67: the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. J Neural Transm 110:803–812

    PubMed  CAS  Google Scholar 

  40. Kanner L (1943) Autistic disturbances of affective contact. Nerv Child 2:217–250

    Google Scholar 

  41. Katz J, Nielsen KM, Soghomonian JJ (2005) Comparative effects of acute or chronic administration of levodopa to 6-hydroxydopamine-lesioned rats on the expression of glutamic acid decarboxylase in the neostriatum and GABAA receptors subunits in the substantia nigra pars reticulata. Neurosci 132(3):833–842

    Article  CAS  Google Scholar 

  42. Kaufman DL, Houser CR, Tobin AJ (1991) Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J Neurochem 56(2):720–723

    Article  PubMed  CAS  Google Scholar 

  43. Kemper TL, Bauman ML (1998) Neuropathology of infantile autism. J Neuropathol Exp Neurol 57(7):645–652

    PubMed  CAS  Google Scholar 

  44. Kern JK (2003) Purkinje cell vulnerability and autism: a possible etiological connection. Brain Dev 25(6):377–382

    Article  PubMed  Google Scholar 

  45. Laprade N, Soghomonian JJ (1995) Differential regulation of mRNA levels encoding for the two isoforms of glutamate decarboxylase (GAD65 and GAD67) by dopamine receptors in the rat striatum. Brain Res Mol Brain Res 34(1):65–74

    Article  PubMed  CAS  Google Scholar 

  46. Lauder JM, Han VKM, Henderson P, Verdoorn T, Towle AC (1986) Prenatal ontogeny of the GABAergic system in the rat brain: an immunocytochemical study. Neurosci 2:4658–4693

    Google Scholar 

  47. Lauritsen M, Mors O, Mortensen PB, Ewald H (1999) Infantile autism and associated autosomal chromosome abnormalities: a register-based study and a literature survey. J Child Psychol Psych 40(3):335–345

    Article  CAS  Google Scholar 

  48. Legay F, Pelhate S, Tappaz M.L. (1982) Phylogenesis of brain glutamic acid decarboxylase from vertebrates: Immunohistochemical studies. J Neurochem 46:1478–1486

    Article  Google Scholar 

  49. Levisohn L, Cronin-golomb A, Schmahmann JD (2000) Neuropsychological consequence of cerebellar tumor resection in children: cerebellar cognitive affective syndrome in a pediatric population. Brain 123:1041–1050

    Article  PubMed  Google Scholar 

  50. Lipska BK, Weinberger DR (2000) To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacol 23(3):223–239

    Article  CAS  Google Scholar 

  51. Llinas RR, Walton KD, Lang EJ (2003) Cerebellum. In: Shepherd GM (eds) The synaptic organization of the brain, 5th ed. Oxford University Press, New York, pp 271–309

    Google Scholar 

  52. Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, Delong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA (2005) Identification of significant association and gene–gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet 77:377–388

    Article  PubMed  CAS  Google Scholar 

  53. Maddox LO, Menold MM, Bass MP, Rogala AR, Pericak-Vance MA, Vance JM, Gilbert JR (1999) Autistic disorder and chromosome 15q11-q13: construction and analysis of a BAC/PAC contig. Genomics 62(3):325–331

    Article  PubMed  CAS  Google Scholar 

  54. Maniatis T, Frisch EF, Sambrook P (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, New York

    Google Scholar 

  55. Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA, Zimmerman A, Gilbert JR, Vance JM, Maddox LO, Wright HH, Abramson RK, Delong GR, Cuccaro ML, Pericak-Vance MA (2000) Analysis of linkage disequilibrium in GABA receptor subunit genes in autistic disorder. Am J Med Genet 96:43–48

    Article  PubMed  Google Scholar 

  56. Mari M, Castiello U, Marks D, Marraffa C, Prior M (2003) The reach to grasp movement in children with autism spectrum disorder. Phil Trans R. Soc Lond B 358:393–403

    Article  Google Scholar 

  57. Mariani J (1982) Extent of multiple innervation of Purkinje cells by climbing fibers in the olivocerebellar system of weaver, reeler, and staggerer mutant mice. J Neurobiol 13(2):119–126

    Article  PubMed  CAS  Google Scholar 

  58. Mengod G, Goudsmit E, Probst A, Palacios JM (1992) In situ hybridization in the human hypothalamus. Prog Brain Res 93:45–55

    PubMed  CAS  Google Scholar 

  59. Moffett JR, Palkovits M, Namboodiri A, Neale JH (1994) Comparative distribution of N-acetlyaspartylglutamate and GAD67 in the cerebellum and precerebellar nuclei of the rat utilizing enhanced carboiimide fixation and immunohistochemistry. J Comp Neurol 347(4):598–618

    Article  PubMed  CAS  Google Scholar 

  60. Muhle R, Trentacoste SV, Rapin I (2004) The genetics of autism. Pediatrics 113(5):472–486

    Article  Google Scholar 

  61. Olney JW, Farber NB (1995) NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacol 13(4):335–345

    Article  CAS  Google Scholar 

  62. Palacios JM, Mengod G (1992) Visualization of neurotransmitter receptors and their mRNAs in the human brain. Arzneimittelforschung 42(2A):189–195

    PubMed  CAS  Google Scholar 

  63. Palay SL, Chan-Palay V (1974) Cerebellar cortex: cytology and organization. Springer, Berlin Heidelberg New York

    Google Scholar 

  64. Philippe A, Martinez M, Bataille-Guillot M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergerm LV, Penet C, Feingold J, Brice A, Leboyer M, the Paris Autism Research International Sibpair study. (1999) An autosomal genomic screen for autism. Collaborative linkage study of autism. Am J Hum Genet 68:1514–1520

    Google Scholar 

  65. Pierce K, Courchesne E (2001) Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psych 49:655–664

    Article  CAS  Google Scholar 

  66. Preece P, Virley DJ, Costandi M, Coombes R, Moss SJ, Mudge AW, Jazin E, Cairns NJ (2003) An optimistic view for quantifying mRNA in post mortem human brain. Mol Brain Res 116:7–16

    Article  PubMed  CAS  Google Scholar 

  67. Rabionet R, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, Delong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Pericak-Vance MA (2004) Analysis of the autism chromosome 2 linkage region: GAD1 and other candidate genes. Neurosci Lett 372:209–214

    Article  PubMed  CAS  Google Scholar 

  68. Ramnani N (2006) The primate cortico-cerebellar system—anatomy and function. Nat Neurosci Rev 7(7):511–522

    Article  CAS  Google Scholar 

  69. Rapin I (1991) Autistic children: diagnosis and clinical feature. Pediatrics 87:751–760

    PubMed  CAS  Google Scholar 

  70. Rapin I, Katzman R (1998) Neurobiology of autism. Ann Neurol 43(1):7–14

    Article  PubMed  CAS  Google Scholar 

  71. Rimvall K, Sheikh SN, Martin DL (1993) Effects of increased γ-aminobutyric acid levels on GAD67 protein and mRNA levels in rat cerebral cortex. J Neurochem 60:714–720

    Article  PubMed  CAS  Google Scholar 

  72. Rimvall K, Martin DL (1994) The level of GAD67 protein is highly sensitive to small increases in intraneuronal γ-aminobutyric acid levels. J Neurochem 62:1375–1381

    Article  PubMed  CAS  Google Scholar 

  73. Rinehart NJ, Bradshaw JL, Brereton AV, Tonge BJ (2001) Movement preparation in high functioning autism and Asperger disorder: a serial choice reaction time task involving motor reprogramming. J Autism Dev Disord 31(1):79–88

    Article  PubMed  CAS  Google Scholar 

  74. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Herbert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Petersen PB, Pingree C, McMahon W, Wong DL, Cavalli-Sforza LL, Kraemer HC, Myers RM (1999) A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 65(2):493–507

    Article  PubMed  CAS  Google Scholar 

  75. Riva D, Giorgi (2000) The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumors. Brain 123:1051–1061

    Article  PubMed  Google Scholar 

  76. Schmahmann JD, Doyon J, Toga AW, Petrides M, Evans AC (2000) MRI atlas of the cerebellum. Academic, New York

    Google Scholar 

  77. Schmahmann JD, Kiliany RJ, Moore TL, DeMong C, MacMore JP, Moss MB (2004) Cerebellar dentate nucleus lesions impair flexibility but not motor function in monkeys. Soc Neurosci Abstr 34:254–312

    Google Scholar 

  78. Schroer RJ, Phelan MC, Michaelis RC, Crawford EC, Skinner SA, Cuccaro M, Simensen RJ, Bishop J, Skinner C, Fender D, Stevensone RE (1998) Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet 76:327–336

    Article  PubMed  CAS  Google Scholar 

  79. Segovia J, Tillakaratne NJ, Whelan K, Tobin AJ, Gale K (1990) Parallel increases in striatal glutamic acid decarboxylase activity and mRNA levels in rats with lesions of the nigrostriatal pathway. Brain Res 529:345–348

    Article  PubMed  CAS  Google Scholar 

  80. Shao Y, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA, Bass MP, McClain C, Von Wendt L, Vance JM, Abramson RH, Wright HH, Ashley-Koch A, Gilbert JR, DeLong RG, Cuccaro ML, Pericak-Vance MA (2002) Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 114:99–105

    Article  PubMed  Google Scholar 

  81. Stuhmer T, Anderson SA, Ekker M, Rubenstein KL (2002) Ectopic expression of the DLX genes induces glutamic acid decarboxylase and DLX expression. Development 129:245–252

    PubMed  CAS  Google Scholar 

  82. Soghomonian JJ, Gonzales C, Chesselet MF (1992) Messenger RNAs encoding glutamate-decarboxylases are differentially affected by nigrostriatal lesions in subpopulations of striatal neurons. Brain Res 576(1):68–79

    Article  PubMed  CAS  Google Scholar 

  83. Soghomonian JJ (1993) Effects of neonatal 6-hydroxydopamine injections on glutamate decarboxylase, preproenkephalin and dopamine D2 receptor mRNAs in the adult rat striatum. Brain Res 621:249–259

    Article  PubMed  CAS  Google Scholar 

  84. Soghomonian JJ, Pedneault S, Audet G, Parent A (1994) Increased glutamate decarboxylase mRNA levels in the striatum and pallidum of MPTP-treated primates. J Neurosci 14:6256–6265

    PubMed  CAS  Google Scholar 

  85. Soghomonian JJ, Laprade N (1997) Glutamate decarboxylase (GAD67 and GAD65) gene expression is increased in a subpopulation of neurons in the putamen of Parkinsonian monkeys. Synapse 27:122–132

    Article  PubMed  CAS  Google Scholar 

  86. Soghomonian JJ, Martin DL (1998) Two isoforms of glutamate decarboxylase: why? Trends Pharmacol Sci 19(12):500–505

    Article  PubMed  CAS  Google Scholar 

  87. Teune TM, Van der Burg J, Van der Moer J, Voodg J, Ruigrok TJ (2000) Topography of cerebellar nuclear projections to the brain stem in the rat. Prog Brain Res 124:141–172

    Article  PubMed  CAS  Google Scholar 

  88. Torrey FF, Barci BM, Webster MJ, Bartko JJ, Meador-Woodruff JH, Knable MB (2005) Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains. Biol Psych 57(3):252–260

    Article  CAS  Google Scholar 

  89. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA (2000) Decreased glutamic acid decoarbosylase 67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 57(3):237–245

    Article  PubMed  CAS  Google Scholar 

  90. Walker E, McNicol AM (1992) In situ hybridization demonstrates the stability of mRNA in post mortem rat tissues. J Pathol 168(1):67–73

    Article  PubMed  CAS  Google Scholar 

  91. Welsh JP, Yuen G, Placantonakis DG, Vu TQ, Haiss F, O’Hearn E, Molliver ME, Aicher SA (2002) Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4 and the cerebellar contribution to post-hypoxic myoclnus. Adv Neurol 89:331–359

    PubMed  Google Scholar 

  92. Whitney ER, Kemper TL, Bauman ML, Blatt GJ (2004) Calcium binding proteins in cerebellar Purkinje cells in autistic cerebellum. Soc Neurosci Abstr 34:116.11

    Google Scholar 

  93. Willcutts MD, Griffin WST, Morrison-Bogorad M (1989) Analysis of glutamic acid decarboxylase mRNA levels during cerebellar development in rat. Neurosci Res Commun 6:57–65

    Google Scholar 

  94. Willcutts MD, Morrison-Bogorad M (1991) Quantitative in situ hybridization analysis of glutamic acid decarboxylase messenger RNA in developing rat cerebellum. Dev Brain Res 63:253–164

    Article  CAS  Google Scholar 

  95. Woo TU, Walsh JP, Benes FM (2004) Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-d-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry 61(7):649–657

    Article  PubMed  CAS  Google Scholar 

  96. Yip J, Marcon R, Kemper TL, Bauman ML, Blatt GJ. (2005): The olivocerebellar projection in autism: using the intermediate filament protein peripherin as a marker for climbing fibers. International Meeting for Autism Res Abstr (IMFAR) 5:49

    Google Scholar 

  97. Yip J, Soghomonian JJ, Bauman M, Kemper T, Blatt GJ (2006) Functional status of the cerebellar Purkinje cells in autistic brains. International Meeting for Autism Research (IMFAR) 5:142

    Google Scholar 

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Acknowledgments

We gratefully acknowledge the Harvard Brain Tissue Resource Center, the Autism Tissue Program (ATP) and the University of Miami and Maryland Brain Banks for providing brain tissues for this study. This work is supported by grants NIH NICHD #HD39459-04 and the Hussman Foundation (GJB, P.I.). We thank Linh Nguyen for her excellent technical assistance with in situ hybridization and Rita Marcon for assistance with tissue cutting.

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  1. Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany St, R1003, Boston, MA, 02118, USA

    Jane Yip, Jean-Jacques Soghomonian & Gene J. Blatt

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  1. Jane Yip
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Yip, J., Soghomonian, JJ. & Blatt, G.J. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol 113, 559–568 (2007). https://doi.org/10.1007/s00401-006-0176-3

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