Hostname: page-component-8448b6f56d-c4f8m Total loading time: 0 Render date: 2024-04-16T18:46:36.081Z Has data issue: false hasContentIssue false
  • English
  • Français

Does microglial dysfunction play a role in autism and Rett syndrome?

Published online by Cambridge University Press:  30 April 2012

Izumi Maezawa ,
Marco Calafiore ,
Heike Wulff  and
Lee-Way Jin
Izumi Maezawa*
Affiliation:
M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Instituteand Department of Pathology and Laboratory Medicine, Sacramento, CA, USA
Marco Calafiore
Affiliation:
M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Instituteand Department of Pathology and Laboratory Medicine, Sacramento, CA, USA
Heike Wulff
Affiliation:
Department of Pharmacology, University of California Davis, Davis, CA, USA
Lee-Way Jin*
Affiliation:
M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Instituteand Department of Pathology and Laboratory Medicine, Sacramento, CA, USA Alzheimer's Disease Center, University of California Davis Medical Center, Sacramento, CA, USA
*
Correspondence should be addressed to: Izumi Maezawa or Lee-Way Jin, Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA 95817USA phone: 916-703-0272 or 916-703-0392 email: imaezawa@ucdavis.edu or lee-way.jin@ucdmc.ucdavis.edu
Correspondence should be addressed to: Izumi Maezawa or Lee-Way Jin, Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA 95817USA phone: 916-703-0272 or 916-703-0392 email: imaezawa@ucdavis.edu or lee-way.jin@ucdmc.ucdavis.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies.

Keywords

Synaptic plasticityepigenetic regulationMeCP2environmentmitochondria
Type
Reviews
Information
Neuron Glia Biology , Volume 7 , Special Issue 1: The Physiological Function of Microglia , February 2011 , pp. 85 - 97
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Altevogt, B.M., Hanson, S.L. and Leshner, A.I. (2008) Autism and the environment: challenges and opportunities for research. Pediatrics 121, 1225–1229.Google Scholar
Alvarez-Saavedra, M., Saez, M.A., Kang, D., Zoghbi, H.Y. and Young, J.I. (2007) Cell-specific expression of wild-type MeCP2 in mouse models of Rett syndrome yields insight about pathogenesis. Human Molecular Genetics 16, 2315–2325.CrossRefGoogle ScholarPubMed
Amaral, D.G. (2011) The promise and the pitfalls of autism research: an introductory note for new autism researchers. Brain Research 1380, 3–9.CrossRefGoogle ScholarPubMed
Antony, J.M., Paquin, A., Nutt, S.L., Kaplan, D.R. and Miller, F.D. (2011) Endogenous microglia regulate development of embryonic cortical precursor cells. Journal of Neuroscience Research 89, 286–298.CrossRefGoogle ScholarPubMed
Armstrong, D.D. (2005) Neuropathology of Rett syndrome. Journal of Child Neurology 20, 747–753.CrossRefGoogle ScholarPubMed
Baccarelli, A. and Bollati, V. (2009) Epigenetics and environmental chemicals. Current Opinion in Pediatrics 21, 243–251.Google Scholar
Ballas, N., Lioy, D.T., Grunseich, C. and Mandel, G. (2009) Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nature Neuroscience 12, 311–317.CrossRefGoogle ScholarPubMed
Barrientos, R.M., Frank, M.G., Crysdale, N.Y., Chapman, T.R., Ahrendsen, J.T., Day, H.E. et al. (2011) Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. Journal of Neuroscience 31, 11578–11586.CrossRefGoogle ScholarPubMed
Battista, D., Ferrari, C.C., Gage, F.H. and Pitossi, F.J. (2006) Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus. European Journal of Neuroscience 23, 83–93.CrossRefGoogle ScholarPubMed
Bauman, M. and Kemper, T.L. (1985) Histoanatomic observations of the brain in early infantile autism. Neurology 35, 866–874.Google Scholar
Belichenko, N.P., Belichenko, P.V. and Mobley, W.C. (2009) Evidence for both neuronal cell autonomous and nonautonomous effects of methyl-CpG-binding protein 2 in the cerebral cortex of female mice with Mecp2 mutation. Neurobiology of Disease 34, 71–77.Google Scholar
Ben Achour, S. and Pascual, O. (2010) Glia: the many ways to modulate synaptic plasticity. Neurochemistry International 57, 440–445.CrossRefGoogle ScholarPubMed
Bessis, A., Bechade, C., Bernard, D. and Roumier, A. (2007) Microglial control of neuronal death and synaptic properties. Glia 55, 233–238.CrossRefGoogle ScholarPubMed
Betancur, C., Sakurai, T. and Buxbaum, J.D. (2009) The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends in Neurosciences 32, 402–412.CrossRefGoogle ScholarPubMed
Blinzinger, K. and Kreutzberg, G. (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Zeitschrift fur Zellforschung und Mikroskopische Anatomie 85, 145–157.Google Scholar
Block, M.L., Zecca, L. and Hong, J.S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews. Neuroscience 8, 57–69.Google Scholar
Borrelli, E., Nestler, E.J., Allis, C.D. and Sassone-Corsi, P. (2008) Decoding the epigenetic language of neuronal plasticity. Neuron 60, 961–974.Google Scholar
Braunschweig, D., Simcox, T., Samaco, R.C. and Lasalle, J.M. (2004) X-Chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett syndrome and Mecp2−/+ mouse brain. Human Molecular Genetics 13, 1275–1286.Google Scholar
Centonze, D., Muzio, L., Rossi, S., Cavasinni, F., De Chiara, V., Bergami, A. et al. (2009) Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. Journal of Neuroscience 29, 3442–3452.CrossRefGoogle ScholarPubMed
Chahrour, M., Jung, S.Y., Shaw, C., Zhou, X., Wong, S.T., Qin, J. et al. (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229.Google Scholar
Chahrour, M. and Zoghbi, H.Y. (2007) The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437.CrossRefGoogle ScholarPubMed
Chamak, B., Dobbertin, A. and Mallat, M. (1995) Immunohistochemical detection of thrombospondin in microglia in the developing rat brain. Neuroscience 69, 177–187.CrossRefGoogle ScholarPubMed
Charleston, J.S., Body, R.L., Mottet, N.K., Vahter, M.E. and Burbacher, T.M. (1995) Autometallographic determination of inorganic mercury distribution in the cortex of the calcarine sulcus of the monkey Macaca fascicularis following long-term subclinical exposure to methylmercury and mercuric chloride. Toxicology and Applied Pharmacology 132, 325–333.CrossRefGoogle ScholarPubMed
Chauhan, A., Gu, F., Essa, M.M., Wegiel, J., Kaur, K., Brown, W.T. et al. (2011) Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. Journal of Neurochemistry 117, 209–220.Google Scholar
Chez, M.G., Dowling, T., Patel, P.B., Khanna, P. and Kominsky, M. (2007) Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatric Neurology 36, 361–365.CrossRefGoogle ScholarPubMed
Choi, S.H., Veeraraghavalu, K., Lazarov, O., Marler, S., Ransohoff, R.M., Ramirez, J.M. et al. (2008) Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron 59, 568–580.Google Scholar
Christopherson, K.S., Ullian, E.M., Stokes, C.C., Mullowney, C.E., Hell, J.W., Agah, A. et al. (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433.CrossRefGoogle ScholarPubMed
Coker, S.B. and Melnyk, A.R. (1991) Rett syndrome and mitochondrial enzyme deficiencies. Journal of Child Neurology 6, 164–166.CrossRefGoogle ScholarPubMed
Colton, C.A. (2009) Heterogeneity of microglial activation in the innate immune response in the brain. Journal of Neuroimmune Pharmacology 4, 399–418.CrossRefGoogle ScholarPubMed
Colton, C.A. and Wilcock, D.M. (2010) Assessing activation states in microglia. CNS & Neurological Disorders Drug Targets 9, 174–191.CrossRefGoogle ScholarPubMed
Connolly, A.M., Chez, M., Streif, E.M., Keeling, R.M., Golumbek, P.T., Kwon, J.M. et al. (2006) Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau–Kleffner syndrome, and epilepsy. Biological Psychiatry 59, 354–363.Google Scholar
Cornford, M.E., Philippart, M., Jacobs, B., Scheibel, A.B. and Vinters, H.V. (1994) Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain. Journal of Child Neurology 9, 424–431.CrossRefGoogle ScholarPubMed
Courchesne, E., Karns, C.M., Davis, H.R., Ziccardi, R., Carper, R.A., Tigue, Z.D. et al. (2001) Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology 57, 245–254.CrossRefGoogle ScholarPubMed
Courchesne, E., Pierce, K., Schumann, C.M., Redcay, E., Buckwalter, J.A., Kennedy, D.P. et al. (2007) Mapping early brain development in autism. Neuron 56, 399–413.CrossRefGoogle ScholarPubMed
Dalmau, I., Finsen, B., Zimmer, J., Gonzalez, B. and Castellano, B. (1998) Development of microglia in the postnatal rat hippocampus. Hippocampus 8, 458–474.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
Dalmau, I., Vela, J.M., Gonzalez, B., Finsen, B. and Castellano, B. (2003) Dynamics of microglia in the developing rat brain. Journal of Comparative Neurology 458, 144–157.CrossRefGoogle ScholarPubMed
Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S. et al. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 8, 752–758.CrossRefGoogle ScholarPubMed
De Felice, C., Ciccoli, L., Leoncini, S., Signorini, C., Rossi, M., Vannuccini, L. et al. (2009) Systemic oxidative stress in classic Rett syndrome. Free Radical Biology and Medicine 47, 440–448.Google Scholar
Dementieva, Y.A., Vance, D.D., Donnelly, S.L., Elston, L.A., Wolpert, C.M., Ravan, S.A. et al. (2005) Accelerated head growth in early development of individuals with autism. Pediatric Neurology 32, 102–108.Google Scholar
Dotti, M.T., Manneschi, L., Malandrini, A., De Stefano, N., Caznerale, F. and Federico, A. (1993) Mitochondrial dysfunction in Rett syndrome. An ultrastructural and biochemical study. Brain & Development 15, 103–106.Google Scholar
Ekdahl, C.T., Kokaia, Z. and Lindvall, O. (2009) Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 158, 1021–1029.Google Scholar
Eter, N., Engel, D.R., Meyer, L., Helb, H.M., Roth, F., Maurer, J. et al. (2008) In vivo visualization of dendritic cells, macrophages, and microglial cells responding to laser-induced damage in the fundus of the eye. Investigative Ophthalmology and Visual Science 49, 3649–3658.Google Scholar
Faraco, G., Pittelli, M., Cavone, L., Fossati, S., Porcu, M., Mascagni, P. et al. (2009) Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiology of Disease 36, 269–279.CrossRefGoogle ScholarPubMed
Forman, M.S., Lal, D., Zhang, B., Dabir, D.V., Swanson, E., Lee, V.M. et al. (2005) Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. Journal of Neuroscience 25, 3539–3550.CrossRefGoogle ScholarPubMed
Frye, R.E. and Rossignol, D.A. (2011) Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatric Research 69, 41R–47R.CrossRefGoogle ScholarPubMed
Garg, T.K. and Chang, J.Y. (2006) Methylmercury causes oxidative stress and cytotoxicity in microglia: attenuation by 15-deoxy-delta 12, 14-prostaglandin J2. Journal of Neuroimmunology 171, 17–28.Google Scholar
Geschwind, D.H. (2008) Autism: many genes, common pathways? Cell 135, 391–395.Google Scholar
Geschwind, D.H. (2011) Genetics of autism spectrum disorders. Trends in Cognitive Sciences 15, 409–416.Google Scholar
Giacometti, E., Luikenhuis, S., Beard, C. and Jaenisch, R. (2007) Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proceedings of the National Academy of Sciences of the U.S.A. 104, 1931–1936.CrossRefGoogle ScholarPubMed
Gibbons, H.M., Smith, A.M., Teoh, H.H., Bergin, P.M., Mee, E.W., Faull, R.L. et al. (2011) Valproic acid induces microglial dysfunction, not apoptosis, in human glial cultures. Neurobiology of Disease 41, 96–103.CrossRefGoogle Scholar
Gibson, J.H., Slobedman, B., Harikrishnan, K.N., Williamson, S.L., Minchenko, D., El-Osta, A. et al. (2010) Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain. BMC Neuroscience 11, 53.Google Scholar
Gilman, S.R., Iossifov, I., Levy, D., Ronemus, M., Wigler, M. and Vitkup, D. (2011) Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70, 898–907.CrossRefGoogle ScholarPubMed
Giulivi, C., Zhang, Y.F., Omanska-Klusek, A., Ross-Inta, C., Wong, S., Hertz-Picciotto, I. et al. (2010) Mitochondrial dysfunction in autism. Journal of the American Medical Association 304, 2389–2396.CrossRefGoogle ScholarPubMed
Goines, P., Haapanen, L., Boyce, R., Duncanson, P., Braunschweig, D., Delwiche, L. et al. (2011) Autoantibodies to cerebellum in children with autism associate with behavior. Brain, Behavior, and Immunity 25, 514–523.CrossRefGoogle ScholarPubMed
Graeber, M.B. (2010) Changing face of microglia. Science 330, 783–788.CrossRefGoogle ScholarPubMed
Greco, C.M., Navarro, C.S., Hunsaker, M.R., Maezawa, I., Shuler, J.F., Tassone, F. et al. (2011) Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome. Molecular Autism 2, 2.Google Scholar
Gupta, S., Aggarwal, S., Rashanravan, B. and Lee, T. (1998) Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. Journal Neuroimmunology 85, 106–109.Google Scholar
Guy, J., Gan, J., Selfridge, J., Cobb, S. and Bird, A. (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147.CrossRefGoogle Scholar
Guy, J., Hendrich, B., Holmes, M., Martin, J.E. and Bird, A. (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nature Genetics 27, 322–326.CrossRefGoogle ScholarPubMed
Hagerman, R., Hoem, G. and Hagerman, P. (2010) Fragile X and autism: intertwined at the molecular level leading to targeted treatments. Molecular Autism 1, 12.CrossRefGoogle ScholarPubMed
Hallmayer, J., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T. et al. (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Archives of General Psychiatry 68, 1095–1102.CrossRefGoogle ScholarPubMed
Hamberger, A., Gillberg, C., Palm, A. and Hagberg, B. (1992) Elevated CSF glutamate in Rett syndrome. Neuropediatrics 23, 212–213.CrossRefGoogle ScholarPubMed
Heilstedt, H.A., Shahbazian, M.D. and Lee, B. (2002) Infantile hypotonia as a presentation of Rett syndrome. American Journal of Medical Genetics 111, 238–242.CrossRefGoogle ScholarPubMed
Hickman, S.E., Allison, E.K. and El Khoury, J. (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. Journal of Neuroscience 28, 8354–8360.Google Scholar
Horska, A., Farage, L., Bibat, G., Nagae, L.M., Kaufmann, W.E., Barker, P.B. et al. (2009) Brain metabolism in Rett syndrome: age, clinical, and genotype correlations. Annals of Neurology 65, 90–97.Google Scholar
Hoshino, Y., Kaneko, M., Yashima, Y., Kumashiro, H., Volkmar, F.R. and Cohen, D.J. (1987) Clinical features of autistic children with setback course in their infancy. Japanese Journal of Psychiatry and Neurology 41, 237–245.Google Scholar
Jayakumar, A.R., Rama Rao, K.V., Schousboe, A. and Norenberg, M.D. (2004) Glutamine-induced free radical production in cultured astrocytes. Glia 46, 296–301.Google Scholar
Jellinger, K.A. (2003) Rett syndrome – an update. Journal of Neural Transmission 110, 681–701.CrossRefGoogle ScholarPubMed
Johnstone, R.W. (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Reviews. Drug Discovery 1, 287–299.Google Scholar
Jones, P.L., Veenstra, G.J., Wade, P.A., Vermaak, D., Kass, S.U., Landsberger, N. et al. (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genetics 19, 187–191.Google Scholar
Jugloff, D.G., Vandamme, K., Logan, R., Visanji, N.P., Brotchie, J.M. and Eubanks, J.H. (2008) Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice. Human Molecular Genetics 17, 1386–1396.Google Scholar
Jyonouchi, H., Sun, S. and Le, H. (2001) Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. Journal Neuroimmunology 120, 170–179.Google Scholar
Kanner, L. and Eisenberg, L. (1958) Child psychiatry, mental deficiency. American Journal of Psychiatry 114, 609–615.Google Scholar
Kemper, T.L. and Bauman, M. (1998) Neuropathology of infantile autism. Journal of Neuropathology and Experimental Neurology 57, 645–652.CrossRefGoogle ScholarPubMed
Kern, J.K. and Jones, A.M. (2006) Evidence of toxicity, oxidative stress, and neuronal insult in autism. Journal of Toxicology and Environmental Health. Part B, Critical Reviews 9, 485–499.Google Scholar
Kettenmann, H., Hanisch, U.K., Noda, M. and Verkhratsky, A. (2011) Physiology of microglia. Physiological Reviews 91, 461–553.CrossRefGoogle ScholarPubMed
Kim, J.V., Jiang, N., Tadokoro, C.E., Liu, L., Ransohoff, R.M., Lafaille, J.J. et al. (2010) Two-photon laser scanning microscopy imaging of intact spinal cord and cerebral cortex reveals requirement for CXCR6 and neuroinflammation in immune cell infiltration of cortical injury sites. Journal of Immunological Methods 352, 89–100.CrossRefGoogle ScholarPubMed
Kishi, N. and Macklis, J.D. (2004) MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Molecular and Cellular Neurosciences 27, 306–321.Google Scholar
Kriaucionis, S., Paterson, A., Curtis, J., Guy, J., Macleod, N. and Bird, A. (2006) Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Molecular and Cellular Biology 26, 5033–5042.Google Scholar
Kurita, H. (1985) Infantile autism with speech loss before the age of thirty months. Journal of the American Academy of Child Psychiatry 24, 191–196.Google Scholar
Landrigan, P.J. (2010) What causes autism? Exploring the environmental contribution. Current Opinion in Pediatrics 22, 219–225.Google Scholar
Lappalainen, R. and Riikonen, R.S. (1996) High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatric Neurology 15, 213–216.Google Scholar
Lasalle, J.M. (2011) A genomic point-of-view on environmental factors influencing the human brain methylome. Epigenetics 6, 862–869.Google Scholar
Lasalle, J.M. and Yasui, D.H. (2009) Evolving role of MeCP2 in Rett syndrome and autism. Epigenomics 1, 119–130.Google Scholar
Leblanc, J.J. and Fagiolini, M. (2011) Autism: a “critical period” disorder? Neural Plasticity 2011, 921680.Google Scholar
Levitt, P. and Campbell, D.B. (2009) The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. Journal of Clinical Investigation 119, 747–754.Google Scholar
Lioy, D.T., Garg, S.K., Monaghan, C.E., Raber, J., Foust, K.D., Kaspar, B.K. et al. (2011) A role for glia in the progression of Rett's syndrome. Nature 475, 497–500.Google Scholar
Lokensgard, J.R., Hu, S., Van Fenema, E.M., Sheng, W.S. and Peterson, P.K. (2000) Effect of thalidomide on chemokine production by human microglia. Journal of Infectious Diseases 182, 983–987.CrossRefGoogle ScholarPubMed
Luikenhuis, S., Giacometti, E., Beard, C.F. and Jaenisch, R. (2004) Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proceedings of the National Academy of Sciences of the U.S.A. 101, 6033–6038.Google Scholar
Luo, Y., Shan, G., Guo, W., Smrt, R.D., Johnson, E.B., Li, X. et al. (2010) Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells. PLoS Genetics 6, e1000898.CrossRefGoogle ScholarPubMed
Maezawa, I. and Jin, L.W. (2010) Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. Journal of Neuroscience 30, 5346–5356.Google Scholar
Maezawa, I., Swanberg, S., Harvey, D., Lasalle, J.M. and Jin, L.W. (2009) Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. Journal of Neuroscience 29, 5051–5061.Google Scholar
Marin-Teva, J.L., Dusart, I., Colin, C., Gervais, A., Van Rooijen, N. and Mallat, M. (2004) Microglia promote the death of developing Purkinje cells. Neuron 41, 535–547.Google Scholar
McFarlane, H.G., Kusek, G.K., Yang, M., Phoenix, J.L., Bolivar, V.J. and Crawley, J.N. (2008) Autism-like behavioral phenotypes in BTBR T + tf/J mice. Genes, Brain and Behavior 7, 152–163.Google Scholar
McPherson, C.A., Kraft, A.D. and Harry, G.J. (2011) Injury-induced neurogenesis: consideration of resident microglia as supportive of neural progenitor cells. Neurotoxicity Research 19, 341–352.Google Scholar
Minshew, N.J. and Keller, T.A. (2010) The nature of brain dysfunction in autism: functional brain imaging studies. Current Opinion in Neurology 23, 124–130.CrossRefGoogle ScholarPubMed
Miyazaki, K., Narita, N., Sakuta, R., Miyahara, T., Naruse, H., Okado, N. et al. (2004) Serum neurotrophin concentrations in autism and mental retardation: a pilot study. Brain & Development 26, 292–295.CrossRefGoogle ScholarPubMed
Monnet-Tschudi, F. (1998) Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation. Journal of Neuroscience Research 53, 361–367.Google Scholar
Moore, S.J., Turnpenny, P., Quinn, A., Glover, S., Lloyd, D.J., Montgomery, T. et al. (2000) A clinical study of 57 children with fetal anticonvulsant syndromes. Journal of Medical Genetics 37, 489–497.CrossRefGoogle ScholarPubMed
Moreno, J.A., Streifel, K.M., Sullivan, K.A., Legare, M.E. and Tjalkens, R.B. (2009) Developmental exposure to manganese increases adult susceptibility to inflammatory activation of glia and neuronal protein nitration. Toxicological Sciences 112, 405–415.CrossRefGoogle ScholarPubMed
Morgan, J.T., Chana, G., Pardo, C.A., Achim, C., Semendeferi, K., Buckwalter, J. et al. (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biological Psychiatry 68, 368–376.Google Scholar
Mullaney, B.C., Johnston, M.V. and Blue, M.E. (2004) Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain. Neuroscience 123, 939–949.Google Scholar
Mutter, J., Naumann, J., Schneider, R., Walach, H. and Haley, B. (2005) Mercury and autism: accelerating evidence? Neuroendocrinology Letters 26, 439–446.Google Scholar
Nagarajan, R.P., Hogart, A.R., Gwye, Y., Martin, M.R. and Lasalle, J.M. (2006) Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 1, e1–e11.Google Scholar
Nan, X., Ng, H.H., Johnson, C.A., Laherty, C.D., Turner, B.M., Eisenman, R.N. et al. (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389.Google Scholar
Ni, M., Li, X., Yin, Z., Jiang, H., Sidoryk-Wegrzynowicz, M., Milatovic, D. et al. (2010) Methylmercury induces acute oxidative stress, altering Nrf2 protein level in primary microglial cells. Toxicological Sciences 116, 590–603.Google Scholar
Nimmerjahn, A., Kirchhoff, F. and Helmchen, F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318.CrossRefGoogle ScholarPubMed
Onishchenko, N., Karpova, N., Sabri, F., Castren, E. and Ceccatelli, S. (2008) Long-lasting depression-like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercury. Journal of Neurochemistry 106, 1378–1387.CrossRefGoogle ScholarPubMed
Onore, C., Careaga, M. and Ashwood, P. (2012) The role of immune dysfunction in the pathophysiology of autism. Brain, Behavior, and Immunity 26, 383–392.CrossRefGoogle ScholarPubMed
Ott, P., Clemmesen, O. and Larsen, F.S. (2005) Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis. Neurochemistry International 47, 13–18.CrossRefGoogle ScholarPubMed
Paolicelli, R.C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P. et al. (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458.Google Scholar
Pardo, C.A., Vargas, D.L. and Zimmerman, A.W. (2005) Immunity, neuroglia and neuroinflammation in autism. International Review of Psychiatry 17, 485–495.Google Scholar
Perry, E.K., Lee, M.L., Martin-Ruiz, C.M., Court, J.A., Volsen, S.G., Merrit, J. et al. (2001) Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. American Journal of Psychiatry 158, 1058–1066.CrossRefGoogle ScholarPubMed
Pessah, I.N., Seegal, R.F., Lein, P.J., Lasalle, J., Yee, B.K., Van De Water, J. et al. (2008) Immunologic and neurodevelopmental susceptibilities of autism. Neurotoxicology 29, 532–545.Google Scholar
Philippart, M. (1986) Clinical recognition of Rett syndrome. American Journal of Medical Genetics. Supplement 1, 111–118.Google Scholar
Rama Rao, K.V., Jayakumar, A.R. and Norenberg, M.D. (2003) Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine. Neurochemistry International 43, 517–523.Google Scholar
Ramocki, M.B., Peters, S.U., Tavyev, Y.J., Zhang, F., Carvalho, C.M., Schaaf, C.P. et al. (2009) Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Annals of Neurology 66, 771–782.CrossRefGoogle ScholarPubMed
Ransohoff, R.M. and Perry, V.H. (2009) Microglial physiology: unique stimuli, specialized responses. Annual Review of Immunology 27, 119–145.CrossRefGoogle ScholarPubMed
Rasalam, A.D., Hailey, H., Williams, J.H., Moore, S.J., Turnpenny, P.D., Lloyd, D.J. et al. (2005) Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Developmental Medicine and Child Neurology 47, 551–555.Google Scholar
Rice, C. (2009) Prevalence of autism spectrum disorders – Autism and Developmental Disabilities Monitoring Network, United States, (2006) MMWR. Surveillance Summaries. 2009/12/22 ed. Atlanta, GA: Center for Disease Control and Prevention.Google Scholar
Ruch, A., Kurczynski, T.W. and Velasco, M.E. (1989) Mitochondrial alterations in Rett syndrome. Pediatric Neurology 5, 320–323.Google Scholar
Russell, J.C., Blue, M.E., Johnston, M.V., Naidu, S. and Hossain, M.A. (2007) Enhanced cell death in MeCP2 null cerebellar granule neurons exposed to excitotoxicity and hypoxia. Neuroscience 150, 563–574.CrossRefGoogle ScholarPubMed
Schmid, R.S., Tsujimoto, N., Qu, Q., Lei, H., Li, E., Chen, T. et al. (2008) A methyl-CpG-binding protein 2-enhanced green fluorescent protein reporter mouse model provides a new tool for studying the neuronal basis of Rett syndrome. Neuroreport 19, 393–398.Google Scholar
Shahbazian, M.D., Antalffy, B., Armstrong, D.L. and Zoghbi, H.Y. (2002) Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Human Molecular Genetics 11, 115–124.Google Scholar
Sheikh, A.M., Malik, M., Wen, G., Chauhan, A., Chauhan, V., Gong, C.X., et al. (2010) BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. Journal of Neuroscience Research 88, 2641–2647.Google Scholar
Shepherd, G.M. and Katz, D.M. (2011) Synaptic microcircuit dysfunction in genetic models of neurodevelopmental disorders: focus on Mecp2 and Met. Current Opinion in Neurobiology 21, 827–833.Google Scholar
Shin, R.W., Iwaki, T., Kitamoto, T. and Tateishi, J. (1991) Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues. Laboratory Investigation 64, 693–702.Google Scholar
Sierra, C., Vilaseca, M.A., Brandi, N., Artuch, R., Mira, A., Nieto, M. et al. (2001) Oxidative stress in Rett syndrome. Brain & Development 23 (Suppl. 1), S236–S239.Google Scholar
Stence, N., Waite, M. and Dailey, M.E. (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33, 256–266.Google Scholar
Stephenson, D.T., O'Neill, S.M., Narayan, S., Tiwari, A., Arnold, E., Samaroo, H.D. et al. (2011) Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis. Molecular Autism 2, 7.Google Scholar
Stromland, K., Nordin, V., Miller, M., Akerstrom, B. and Gillberg, C. (1994) Autism in thalidomide embryopathy: a population study. Developmental Medicine and Child Neurology 36, 351–356.Google Scholar
Sudhof, T.C. (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911.Google Scholar
Svoboda, N. and Kerschbaum, H.H. (2009) L-Glutamine-induced apoptosis in microglia is mediated by mitochondrial dysfunction. European Journal of Neuroscience 30, 196–206.Google Scholar
Sweeten, T.L., Posey, D.J., Shankar, S. and McDougle, C.J. (2004) High nitric oxide production in autistic disorder: a possible role for interferon-gamma. Biological Psychiatry 55, 434–437.Google Scholar
Takeuchi, H., Jin, S., Wang, J., Zhang, G., Kawanokuchi, J., Kuno, R. et al. (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. Journal of Biological Chemistry 281, 21362–21368.Google Scholar
Trapp, B.D., Wujek, J.R., Criste, G.A., Jalabi, W., Yin, X., Kidd, G.J. et al. (2007) Evidence for synaptic stripping by cortical microglia. Glia 55, 360–368.CrossRefGoogle ScholarPubMed
Tremblay, M.E., Lowery, R.L. and Majewska, A.K. (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biology 8, e1000527.Google Scholar
Van Kooten, I.A., Palmen, S.J., Von Cappeln, P., Steinbusch, H.W., Korr, H., Heinsen, H. et al. (2008) Neurons in the fusiform gyrus are fewer and smaller in autism. Brain 131, 987–999.Google Scholar
Vargas, D.L., Nascimbene, C., Krishnan, C., Zimmerman, A.W. and Pardo, C.A. (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology 57, 67–81.CrossRefGoogle ScholarPubMed
Villafuerte, S. (2011) Suggestive evidence on the genetic link between mitochondria dysfunction and autism. Acta Psychiatrica Scandinavica 123, 95.CrossRefGoogle ScholarPubMed
Volkmar, F.R. and Cohen, D.J. (1989) Disintegrative disorder or “late onset” autism. Journal of Child Psychology and Psychiatry 30, 717–724.Google Scholar
Wakai, S., Kameda, K., Ishikawa, Y., Miyamoto, S., Nagaoka, M., Okabe, M. et al. (1990) Rett syndrome: findings suggesting axonopathy and mitochondrial abnormalities. Pediatric Neurology 6, 339–343.CrossRefGoogle ScholarPubMed
Wake, H., Moorhouse, A.J., Jinno, S., Kohsaka, S. and Nabekura, J. (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. Journal of Neuroscience 29, 3974–3980.CrossRefGoogle ScholarPubMed
Wallace, D.C. and Fan, W. (2010) Energetics, epigenetics, mitochondrial genetics. Mitochondrion 10, 12–31.CrossRefGoogle ScholarPubMed
Wegiel, J., Kuchna, I., Nowicki, K., Imaki, H., Marchi, E., Ma, S.Y. et al. (2010) The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathologica 119, 755–770.CrossRefGoogle ScholarPubMed
Wills, S., Cabanlit, M., Bennett, J., Ashwood, P., Amaral, D.G. and Van De Water, J. (2009) Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain, Behavior, and Immunity 23, 64–74.Google Scholar
Woodward, G. (2001) Autism and Parkinson's disease. Medical Hypotheses 56, 246–249.Google Scholar
Xu, J., Xiao, N. and Xia, J. (2010) Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nature Neuroscience 13, 22–24.Google Scholar
Yasui, D.H., Peddada, S., Bieda, M.C., Vallero, R.O., Hogart, A., Nagarajan, R.P. et al. (2007) Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proceedings of the National Academy of Sciences of the U.S.A. 104, 19416–19421.Google Scholar
Yeargin-Allsopp, M., Rice, C., Karapurkar, T., Doernberg, N., Boyle, C. and Murphy, C. (2003) Prevalence of autism in a US metropolitan area. Journal of the American Medical Association 289, 49–55.Google Scholar
Yirmiya, R. and Goshen, I. (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain, Behavior, and Immunity 25, 181–213.Google Scholar
Zhang, B., West, E.J., Van, K.C., Gurkoff, G.G., Zhou, J., Zhang, X.M. et al. (2008) HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Research 1226, 181–191.CrossRefGoogle Scholar
Zhao, J., Lopez, A.L., Erichsen, D., Herek, S., Cotter, R.L., Curthoys, N.P. et al. (2004) Mitochondrial glutaminase enhances extracellular glutamate production in HIV-1-infected macrophages: linkage to HIV-1 associated dementia. Journal of Neurochemistry 88, 169–180.Google Scholar
Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N. et al. (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neuroscience 9, 268–275.Google Scholar
Zoghbi, H.Y. (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826–830.Google Scholar
Zoghbi, H.Y. (2009) Rett syndrome: what do we know for sure? Nature Neuroscience 12, 239–240.Google Scholar