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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

RETRACTED ARTICLE: Alteration of astrocytes and Wnt/β-catenin signaling in the frontal cortex of autistic subjects

Authors: Fujiang Cao, Ailan Yin, Guang Wen, Ashfaq M Sheikh, Zujaja Tauqeer, Mazhar Malik, Amenah Nagori, Michael Schirripa, Frank Schirripa, George Merz, W Ted Brown, Xiaohong Li

Published in: Journal of Neuroinflammation | Issue 1/2012

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Abstract

Background

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. To date the etiology of this disorder is poorly understood. Studies suggest that astrocytes play critical roles in neural plasticity by detecting neuronal activity and modulating neuronal networks. Recently, a number of studies suggested that an abnormal function of glia/astrocytes may be involved in the development of autism. However, there is yet no direct evidence showing how astrocytes develop in the brain of autistic individuals.

Methods

Study subjects include brain tissue from autistic subjects, BTBR T + tfJ (BTBR) and Neuroligin (NL)-3 knock-down mice. Western blot analysis, Immunohistochemistry and confocal microscopy studies have be used to examine the density and morphology of astrocytes, as well as Wnt and β-catenin protein expression.

Results

In this study, we demonstrate that the astrocytes in autisitcsubjects exhibit significantly reduced branching processes, total branching length and cell body sizes. We also detected an astrocytosis in the frontal cortex of autistic subjects. In addition, we found that the astrocytes in the brain of an NL3 knockdown mouse exhibited similar alterations to what we found in the autistic brain. Furthermore, we detected that both Wnt and β-catenin proteins are decreased in the frontal cortex of autistic subjects. Wnt/β-catenin pathway has been suggested to be involved in the regulation of astrocyte development.

Conclusions

Our findings imply that defects in astrocytes could impair neuronal plasticity and partially contribute to the development of autistic-like behaviors in both humans and mice. The alteration of Wnt/β-catenin pathway in the brain of autistic subjects may contribute to the changes of astrocytes.
Literature
1.
Bolivar VJ, Walters SR, Phoenix JL: Assessing autism-like behavior in mice: variations in social interactions among inbred strains. Behav Brain Res 2007, 176:21–26.CrossRefPubMed
2.
Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, Barbaro JR, Wilson LM, Threadgill DW, Lauder JM, Magnuson TR, Crawley JN: Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 2007, 176:4–20.CrossRefPubMed
3.
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.CrossRefPubMed
4.
Silverman JL, Tolu SS, Barkan CL, Crawley JN: Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 2009, 35:976–989.CrossRefPubMedPubMedCentral
5.
Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC: A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 2007, 318:71–76.CrossRefPubMedPubMedCentral
6.
Kettenmann H, Verkhratsky A: Beta-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. FortschrNeurolPsychiatr 2011, 79:588–597.
7.
Miller FD, Gauthier AS: Timing is everything: making neurons versus glia in the developing cortex. Neuron 2007, 54:357–369.CrossRefPubMed
8.
Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, Gotoh Y: The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 2004, 131:2791–2801.CrossRefPubMed
9.
Israsena N, Hu M, Fu W, Kan L, Kessler JA: The presence of FGF2 signaling determines whether beta-catenin exerts effects on proliferation or neuronal differentiation of neural stem cells. DevBiol 2004, 268:220–231.
10.
Zhou CJ, Borello U, Rubenstein JL, Pleasure SJ: Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway. Neuroscience 2006, 142:1119–1131.CrossRefPubMed
11.
L’episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, Pluchino S, Marchetti B: A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. MolNeurodegener 2011, 6:49.
12.
White BD, Nathe RJ, Maris DO, Nguyen NK, Goodson JM, Moon RT: Beta-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem Cells 2010, 28:297–307.PubMedPubMedCentral
13.
Laurence JA, Fatemi SH: Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum 2005, 4:206–210.CrossRefPubMed
14.
Ahlsén G, Rosengren L, Belfrage M, Palm A, Haglid K, Hamberger A, Gillberg C: Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. Biol Psychiatry 1993, 33:734–743.CrossRefPubMed
15.
Chahrour M, Zoghbi HY: The story of Rett syndrome: from clinic to neurobiology. Neuron 2007, 56:422–437.CrossRefPubMed
16.
Ballas U, Lioy DT, Grunseich C, Mandel G: Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci 2009, 12:311–317.CrossRefPubMedPubMedCentral
17.
Lioy DT, Garg SK, Monaghan CE, Jacob R, Foust KD, Kaspar BK, Hirrlinger PG, Frank K, Bissonnette JM, Ballas N, Mandel G: A role for glia in the progression of Rett’s syndrome. Nature 2011, 475:497–500.CrossRefPubMedPubMedCentral
18.
Shelley J, Meera N, Doering LC: Fragile X astrocytes induce developmental delays in dendrite maturation and synaptic protein expression. BMC Neurosci 2010, 11:132.CrossRef
19.
20.
Fatemi SH, Folsom TD, Reutiman TJ, Lee S: Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism. Synapse 2008, 62:501–507.CrossRefPubMedPubMedCentral
21.
Pekny M, Pekna M: Astrocyte intermediate filaments in CNS pathologies and regeneration. J Pathol 2004, 204:428–437.CrossRefPubMed
22.
Anderová M, Kubinová S, Mazel T, Chvátal A, Eliasson C, Pekny M, Syková E: Effect of elevated K(1), hypotonic stress, and cortical spreading depression on astrocyte swelling in GFAP-deficient mice. Glia 2001, 35:189–203.CrossRefPubMed
23.
Hughes EG, Maguire JL, McMinn MT, Scholz RE, Sutherland M: Loss of glial fibrillary acidic protein results in decreased glutamate transport and inhibition of PKA-induced EAAT2 cell surface trafficking. Brain Res 2004, 124:114–123.CrossRef
24.
Baorto DM, Mellado W, Shelanski ML: Astrocyte process growth induction by actin breakdown. J Cell Biol 1997, 117:357–367.CrossRef
25.
Danbolt NC: Glutamate uptake. ProgNeurobiol 2001, 65:1–105.
26.
Sullivan R, Rauen T, Fischer F, Wiessner M, Grewer C, Bicho A, Pow DV: Cloning, transport properties, and differential localization of two splice variants of GLT-1 in the rat CNS: Implications for CNS glutamate homeostasis. Glia 2004, 45:155–169.CrossRefPubMed
27.
Torres-Platas SG, Christa H, Maria Antonietta Davoli1 , Gilles Maussion1 , Benoit L, Gustavo T, Naguib M: Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology 2011, 36:2650–2658.CrossRefPubMedPubMedCentral
28.
Bechmann I, Galea I, Perry VH: What is the blood–brain barrier (not)? Trends Immunol 2007, 28:5–11.CrossRefPubMed
29.
Farina C, Aloisi F, Meinl E: Astrocytes are active players in cerebral innate immunity. Trends Immunol 2007, 28:138–145.CrossRefPubMed
30.
Herx LM, Yong VW: Interleukin-1b is required for the early evolution of reactive astrogliosis following CNS lesion. J NeuropatholExpNeurol 2001, 60:961–971.CrossRef
31.
Herx LM, Rivest S, Yong VW: Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1b is required for the production of ciliaryneurotrophic factor. J Immunol 2000, 165:2232–2239.CrossRefPubMed
32.
Mason JL, Suzuki K, Chaplin DD, Matsushima GK: Interleukin-1b promotes repair of the CNS. J Neurosci 2001, 21:7046–7052.PubMed
33.
Penkowa M, Moos T, Carrasco J, Hadberg H, Molinero A, Bluethmann H, Hidalgo J: Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice. Glia 1999, 25:343–357.CrossRefPubMed
34.
Swartz KR, Liu F, Sewell D, Schochet T, Campbell I, Sandor M, Fabry Z: Interleukin-6 promotes post-traumatic healing in the central nervous system. Brain Res 2011, 896:86–95.CrossRef
35.
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Brown T, Malik M: Elevated immune response in the brain of autistic patients. J Neuroimmunol 2009, 207:111–116.CrossRefPubMedPubMedCentral
36.
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA: Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005, 57:67–81.CrossRefPubMed
37.
Ashwood P, Wakefield AJ: Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol 2006, 173:126–134.CrossRefPubMed
38.
Jyonouchi H, Sun S, Le H: Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 2001, 120:170–179.CrossRefPubMed
39.
Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M: Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. PediatrNeurol 2007,36(6):361–365.
40.
Ingh VK: Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. J Neuroimmunol 1996, 66:143–145.CrossRef
41.
Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M: Activation of the inflammatory response system in autism. Neuropsychobiology 2002, 45:1–6.CrossRefPubMed
42.
Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, Maher TA, Tager-Flusberg H, Bolliger MF, Carter AS, Boucard AA, Powell CM, Südhof TC: A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci 2009, 29:10843–10854.CrossRefPubMedPubMedCentral
43.
Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M, Gottmann K, Zhang W, Sudhof TC, Brose N: Neuroligins determine synapse maturation and function. Neuron 2006, 51:741–754.CrossRefPubMed
44.
Levinson JN, Li R, Kang R, Moukhles H, El-Husseini A, Bamji SX: Postsynaptic scaffolding molecules modulate the localization of neuroligins. Neuroscience 2010, 165:782–793.CrossRefPubMed
45.
Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM: Neurexins induce differentiation of GAB-1026.
46.
Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR: Xp deletions associated with autism in three females. Hum Genet 1999, 104:43–48.CrossRefPubMed
47.
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T: Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003, 34:27–29.CrossRefPubMedPubMedCentral
48.
Gilbert M, Smith J, Roskams AJ, Auld VJ: Neuroligin 3 is a vertebrate gliotactin expressed in the olfactory ensheathing glia, a growth-promoting class of macroglia. Glia 2001, 34:151–164.CrossRefPubMed
49.
Stephenson DT, O’Neill SM, Narayan S, Tiwari A, Arnold E, Samaroo HD, Du F, Ring RH, Campbell B, Pletcher M, Vaidya VA, Morton D: Histopathologic characterization of the BTBR mouse model of autisticlike behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis. Mol Autism 2011, 2:7.CrossRefPubMedPubMedCentral
50.
51.
Hughes EG, Elmariah SB, Balice-Gordon RJ: Astrocyte secreted proteins selectively increase hippocampal GABAergic axon length, branching, and synaptogenesis. Mol Cell Neurosci 2010, 43:136.CrossRefPubMed
52.
Machon O, Backman M, Machonova O, Kozmik Z, Vacik T, Andersen L, Krauss S: A dynamic gradient of Wnt signaling controls initiation of neurogenesis in the mammalian cortex and cellular specification in the hippocampus. DevBiol 2007, 311:223–237.
53.
Zhou C-J, Zhao C, Pleasure SJ: Wnt signaling mutants have decreased granule cell production and radial glial scaffolding abnormalities. J Neurosci 2004, 24:121–126.CrossRefPubMed
54.
Farias GG, Godoy JA, Cerpa W, Varela-Nallar L, Inestrosa NC: Wnt signaling modulates pre- and postsynaptic maturation: therapeutic considerations. DevDyn 2010, 239:94–101.
55.
Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Jinde S, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N: Association between autism and variants in the wingless-type MMTV integration site family member 2 (WNT2) gene. Int J Neuropsychopharmacol 2010, 13:443–449.CrossRefPubMed
56.
Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield VC: Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 2001, 105:406–413.CrossRefPubMed
Metadata
Title
RETRACTED ARTICLE: Alteration of astrocytes and Wnt/β-catenin signaling in the frontal cortex of autistic subjects
Authors
Fujiang Cao
Ailan Yin
Guang Wen
Ashfaq M Sheikh
Zujaja Tauqeer
Mazhar Malik
Amenah Nagori
Michael Schirripa
Frank Schirripa
George Merz
W Ted Brown
Xiaohong Li
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-223

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