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NeuroMolecular Medicine
Published in: NeuroMolecular Medicine 2/2018

Open Access 01-06-2018 | Review Paper

Neuroimmunologic and Neurotrophic Interactions in Autism Spectrum Disorders: Relationship to Neuroinflammation

Authors: Kshama Ohja, Evelyne Gozal, Margaret Fahnestock, Lu Cai, Jun Cai, Jonathan H. Freedman, Andy Switala, Ayman El-Baz, Gregory Neal Barnes

Published in: NeuroMolecular Medicine | Issue 2/2018

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Abstract

Autism spectrum disorders (ASD) are the most prevalent set of pediatric neurobiological disorders. The etiology of ASD has both genetic and environmental components including possible dysfunction of the immune system. The relationship of the immune system to aberrant neural circuitry output in the form of altered behaviors and communication characterized by ASD is unknown. Dysregulation of neurotrophins such as BDNF and their signaling pathways have been implicated in ASD. While abnormal cortical formation and autistic behaviors in mouse models of immune activation have been described, no one theory has been described to link activation of the immune system to specific brain signaling pathways aberrant in ASD. In this paper we explore the relationship between neurotrophin signaling, the immune system and ASD. To this effect we hypothesize that an interplay of dysregulated immune system, synaptogenic growth factors and their signaling pathways contribute to the development of ASD phenotypes.
Literature
Ahmad, S. F., Nadeem, A., Ansari, M. A., Bakheet, S. A., Attia, S. M., Zoheir, K. M., et al. (2017a). Imbalance between the anti- and pro- inflammatory milieu in blood leukocytes of autistic children. Molecular Immunology, 82, 57–65.PubMedCrossRef
Ahmad, S. F., Zoheir, K. M., Ansari, M. A., Nadeem, A., Bakheet, S. A., Al-Ayadhi, L. Y., et al. (2017b). Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism. Molecular Neurobiolology, 54(6), 4390–4400.CrossRef
Aloisi, F., Ria, F., & Adorin, L. (2000). Regulation of T-cell responses by CNS antigen-presenting cells: Different roles for microglia and astrocytes. Immunology Today, 21(3), 141–147.PubMedCrossRef
Alonso, P., Gratacòs, M., Menchón, J. M., Saiz-Ruiz, J., Segalas, C., Baca-Garcia, E., et al. (2008). Extensive genotyping of the BDNF and NTRK2 genes define protective haplotypes against obsessive-compulsive disorder. Biological Psychiatry, 63(6), 619–628.PubMedCrossRef
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., Text Revision). Washington, DC: Authors.
Aoki, C. A., Borchers, A. T., Li, M., Flavell, R. A., Bowlus, C. L., Ansari, A. A., et al. (2005). Transforming growth factor beta (TGF-beta) and autoimmunity. Autoimmunity Reviews, 4(7), 450–459.PubMedCrossRef
Ashwood, P., Anthony, A., Pellicer, A. A., Torrente, F., Walker-Smith, J. A., & Wakefield, A. J. (2003). Intestinal lymphocyte populations in children with regressive autism: Evidence for extensive mucosal immunopathology. Journal of Clinical Immunology, 23(6), 504–517.PubMedCrossRef
Ashwood, P., Anthony, A., Torrente, F., & Wakefield, A. J. (2004). Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: Mucosal immune activation and reduced counter regulatory interleukin-10. Journal of Clinical Immunology, 24(6), 664–673.PubMedCrossRef
Ashwood, P., Enstrom, A., Krakowiak, P., Hertz-Picciotto, I., Hansen, R. L., Croen, L. A., et al. (2008). Decreased transforming growth factor Beta 1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes. Journal of Neuroimmunology, 204, 149–153.PubMedPubMedCentralCrossRef
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I. N., & Van de Water, J. (2011). Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. Journal of Neuroimmunology, 232(1–2), 196–199.PubMedCrossRef
Bailey, A., Le Counteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzad, E., et al. (1995). Autism as a strongly genetic disorder: Evidence from a British twin study. Psychological Medicine, 25, 63–77.PubMedCrossRef
Bartlett, C. W., Garoni, N., Millonig, J. H., & Brzustiwicz, L. M. (2005). Three autism candidate genes: A synthesis of human genetic analysis with other disciplines. International Journal of Developmental Neuroscience, 23(2–3), 221–234.PubMedCrossRef
Boche, D., Perry, V. H., & Nicoll, J. A. (2013). Review: Activation patterns of microglia and their identification in the human brain. Neuropathology and Applied Neurobiology, 39(1), 3–18.PubMedCrossRef
Bourgeron, T. (2015). From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nature Reviews Neuroscience, 16(9), 551–563.PubMedCrossRef
Caleo, M., & Maffei, L. (2002). Neurotrophins and plasticity in the visual cortex. Neuroscientist, 8(1), 52–61.PubMedCrossRef
Campbell, D. B., Li, C., Sutcliffe, J. S., & Lewitt, P. (2008). Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Research, 1, 159–168.PubMedPubMedCentralCrossRef
Chan, W. Y., Kohsaka, S., & Rezaie, P. (2007). The origin and cell lineage of microglia: New concepts. Brain Research Reviews, 53, 344–354.PubMedCrossRef
Chen, B. Y., Wang, X., Wang, Z. Y., Wang, Y. Z., Chen, L. W., & Luo, Z. J. (2013). Brain-derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/β-catenin signaling pathway. Journal of Neuroscience Research, 91(1), 30–41.PubMed
Chhor, V., Le Charpentier, T., Lebon, S., Ore, M. V., Celador, E. L., Josserand, J., et al. (2013). Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain, Behavior, and Immunity, 32, 70–85.PubMedPubMedCentralCrossRef
Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V., et al. (2016). The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 351(6276), 933–939.PubMedPubMedCentralCrossRef
Cholfin, J. A., & Rubenstein, J. L. (2007). Patterning of frontal cortex subdivisions by Fgf17. Proceedings of the National Academy of Sciences USA, 104(18), 7652–7657.CrossRef
Cohen-Cory, S., & Frazer, S. E. (1995). Effects of brain-derived neurotrophic factor on optic axon branching and remodeling in vivo. Nature, 378, 192–196.PubMedCrossRef
Colvert, E., Tick, B., McEwen, F., Stewart, C., Curran, S. R., Woodhouse, E., et al. (2015). Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample. JAMA Psychiatry, 72(5), 415–423.PubMedPubMedCentralCrossRef
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(4), 354–363.PubMedCrossRef
Correia, C. T., Coutinho, A. M., Sequeira, A. F., Sousa, I. G., Lourenco-Venda, L., Almeida, J. P., et al. (2010). Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes, Brain and Behavior, 9(7), 841–848.CrossRef
Croonenberghs, J., Bosmans, E., Deboutte, D., Kenis, G., & Maes, M. (2002). Activation of the inflammatory response system in autism. Neuropsychobiology, 45(1), 1–6.PubMedCrossRef
Curran, L. K., Newschaffer, C. J., Lee, L. C., Crawford, S. O., Johnston, M. V., & Zimmerman, A. W. (2007). Behaviors associated with fever in children with autism spectrum disorders. Pediatrics, 120(6), e1386–e1392.PubMedCrossRef
De Rubeis, S., He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Cicek, A. E., et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515(7526), 209–215.PubMedPubMedCentralCrossRef
Devlin, B., & Scherer, S. W. (2012). Genetic architecture in autism spectrum disorder. Current Opinion in Genetics & Development, 22(3), 229–237.CrossRef
Dhabhar, F. S. (2014). Effects of stress on immune function: The good, the bad, and the beautiful. Immunology Research, 58, 193–210.CrossRef
Edmiston, E., Ashwood, P., & Van de Water, J. (2017). Autoimmunity, Autoantibodies, and Autism Spectrum Disorder. Biological Psychiatry, 81(5), 383–390.PubMedCrossRef
Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269.PubMedCrossRef
Enstrom, A. M., Lit, L., Onore, C. E., Gregg, J. P., Hansen, R. L., Pessah, I. N., et al. (2009). Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain, Behavior, and Immunity, 23, 124–133.PubMedCrossRef
Enstrom, A. M., Onore, C. E., Van de Water, J. A., et al. (2010). Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain, Behavior, and Immunity, 24(1), 64–71.PubMedCrossRef
Estes, M. L., & McAllister, A. K. (2015). Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nature Reviews in Neuroscience, 16(8), 469–486.PubMedCrossRef
Falk, S., Wurdak, H., Ittner, L. M., Ille, F., Sumara, G., Schmid, M. T., et al. (2008). Brain Area-Specific Effect of TGF-β Signaling on Wnt-Dependent Neural Stem Cell Expansion. Cell Stem Cell, 2(5), 472–483.PubMedCrossRef
Fanous, A. H., Neale, M. C., Straub, R. E., Webb, B. T., O’Neill, A. F., Walsh, D., et al. (2004). Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: A family based association study. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 125B(1), 69–78.CrossRef
Fenner, B. M. (2012). Truncated TrkB: Beyond a dominant negative receptor. Cytokine TrkB signaling and its role in autistic behaviour. Growth Factor Reviews, 23(1–2), 15–24.CrossRef
Flavell, R. A. (1999). The molecular basis of T cell differentiation. Immunological Research, 19, 159–168.CrossRef
Franco, R., & Fernandez-Surarez, D. (2015). Alternatively activated microglia and macrophages in the central nervous system. Progress in Neurobiology, 131, 65–86.PubMedCrossRef
Frazier, T. W., Thompson, L., Youngstrom, E. A., Law, P., Hardan, A. Y., Eng, C., et al. (2014). A twin study of heritable and shared environmental contributions to autism. Journal of Autism and Developmental Disorders, 44(8), 2013–2025.PubMedPubMedCentralCrossRef
Gant, J. C., Thibault, O., Blalock, E. M., Yang, J., Bachstetter, A., Kotick, J., et al. (2009). Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: Implications for autism and epilepsy. Epilepsia, 50(4), 629–645.PubMedCrossRef
Garbett, K., Ebert, P. J., Mitchell, A., Lintas, C., Manzi, B., Mirnics, K., et al. (2008). Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiology of Disease, 30(3), 303–311.PubMedPubMedCentralCrossRef
Garcia, K. L., Yu, G., Nicolini, C., Michalski, B., Garzon, D. J., Chiu, V. S., et al. (2012). Altered Balance of Proteolytic Isoforms of Pro–Brain-Derived Neurotrophic Factor in Autism. Journal of Neuropathology and Experimental Neurology, 71(4), 289–297.PubMedPubMedCentralCrossRef
Gentile, I., Zappulo, E., Militerni, R., Pascotto, A., Borgia, G., & Bravaccio, C. (2013). Etiopathogenesis of autism spectrum disorders: Fitting the pieces of the puzzle together. Medical Hypotheses, 81(1), 26–35.PubMedCrossRef
Gesundheit, B., Rosenzweig, J. P., Naor, D., Lerer, B., Zachor, D. A., Prochazja, V., et al. (2013). Immunological and autoimmune considerations of Autism Spectrum Disorders. Journal of Autoimmunity, 44, 1–7.PubMedCrossRef
Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., et al. (2013). Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature, 493, 371–377.PubMedCrossRef
Goines, P. E., & Ashwood, P. (2013). Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Neurotoxicology and Teratology, 36, 67–81.PubMedCrossRef
Guan, Z., & Fang, J. (2006). Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain, Behavior, and Immunity, 20(1), 64–71.PubMedCrossRef
Gupta, S., Aggarwal, S., Rashanravan, B., & Lee, T. (1998). Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. Journal of Neuroimmunology, 85(1), 106–109.PubMedCrossRef
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(11), 1095–1102.PubMedPubMedCentralCrossRef
Hiester, B. G., Galati, D. F., Salinas, Patricia C., & Jones, K. R. (2013). Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation. Molecular Cellular Neuroscience, 56, 115–127.PubMedPubMedCentralCrossRef
Je, H. S., Yang, F., Ji, Y., Nagappan, G., Heamstead, B. L., & Lu, B. (2012). Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses. Proceedings of the National Academy of Sciences USA, 109, 15924–15929.CrossRef
Jyonouchi, H., Geng, L., & Davidow, A. L. (2014). Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: An inflammatory subtype? Journal of Neuroinflammation, 27(11), 187. https://​doi.​org/​10.​1186/​s12974-014-0187-2.CrossRef
Jyonouchi, H., Geng, L., Streck, D. L., & Toruner, G. A. (2011). Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes. Journal of Neuroimmunology, 238(1–2), 73–80.PubMedCrossRef
Jyonouchi, H., Sun, S., & 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 of Neuroimmunology, 120, 170–179.PubMedCrossRef
Kang, H., & Schuman, E. M. (1995). Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science, 267(5204), 1658–1662.PubMedCrossRef
Kaplan, D. R., & Miller, F. D. (2000). Neurotrophin signal transduction in the nervous system. Current Opinion in Neurobiology, 10(3), 381–391.PubMedCrossRef
Kelleher, R. J., 3rd, & Bear, M. F. (2008). The autistic neuron: Troubled translation? Cell, 135, 401–406.PubMedCrossRef
Krakowiak, P., Goines, P. E., Tancredi, D. J., Ashwood, P., Hansen, R. L., Herz- Picciotto, I., et al. (2017a). Neonatal Cytokine Profiles Associated with Autism Spectrum Disorder. Biological Psychiatry, 81(5), 442–451.PubMedCrossRef
Krakowiak, P., Walker, C. K., Tancredi, D., Hertz-Picciotto, I., & Van de Water, J. (2017b). Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Research, 10(1), 89–98.PubMedCrossRef
Kwan, V., Unda, B. K., & Singh, K. K. (2016). Wnt signaling networks in autism spectrum disorder and intellectual disability. Journal of Neurodevelopmental Disorders, 8, 45. (eCollection 2016. Review).PubMedPubMedCentralCrossRef
Lan, R. Y., Ansari, A. A., Lian, Z. X., & Gershwin, M. E. (2005). Regulatory T cells: Development, function and role in autoimmunity. Autoimmunity Reviews, 4(6), 351–363.PubMedCrossRef
Lee, R., Kermani, P., Teng, K. K., & Hempstead, B. L. (2001). Regulation of cell survival by secreted proneurotrophins. Science, 294(5548), 1945–1948.PubMedCrossRef
Li, X., Chauhan, A., Sheikh, A. M., Patil, S., Chauhan, V., Li, X. M., et al. (2009). Elevated immune response in the brain of autistic patients. Journal of Neuroimmunology, 207(1–2), 111–116.PubMedPubMedCentralCrossRef
Lintas, C., & Persico, A. (2009). Autistic phenotypes and genetic testing: State-of-the-art for the clinical geneticist. Journal of Medical Genetics, 46, 1–8.PubMedCrossRef
Mantel, P. Y., & Schmidt-Weber, C. B. (2011). Transforming growth factor-beta: Recent advances on its role in immune tolerance. Methods in Molecular Biology, 677, 303–338.PubMedCrossRef
Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., & Locati, M. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends in Immunology, 25, 677–686.PubMedCrossRef
Marui, T., Funatogawa, I., Koishi, S., Yamamoto, K., Matsumoto, H., Jinde, S., et al. (2010). Association between autism and variants in the wingless-type MMTV integration site family member 2 (WNT2) gene. International Journal of Neuropsychopharmacology, 13, 443–449.PubMedCrossRef
McAllister, A. K., Lo, D. C., & Katz, L. C. (1995). Neurotrophins regulate dendritic growth in developing visual cortex. Neuron, 115(4), 791–803.CrossRef
McQuillan, K., Lynch, M. A., & Mills, K. H. (2010). Activation of mixed glia by Aβ-specific Th1 and Th17 cells and its regulation by Th2 cells. Brain, Behavior, and Immunity, 24(4), 598–607.PubMedCrossRef
Medzhitov, R., & Janeway, C., Jr. (2000). Innate immunity. New England Journal of Medicine, 343, 338–344.PubMedCrossRef
Memet, S. (2006). NFκB functions in the nervous system: From development to disease. Biochemical Pharmacology, 72, 1180–1195.PubMedCrossRef
Menna, E., Zambetti, S., Morini, R., Donzelli, A., Disanza, A., Calviogioni, D., et al. (2013). Eps8 controls dendritic spine density and synaptic plasticity through its actin-capping activity. EMBO Journal, 32(12), 1730–1744.PubMedPubMedCentralCrossRef
Michalski, B., & Fahnestock, M. (2003). Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Brain Research. Molecular Brain Research, 111(1–2), 148–154.PubMedCrossRef
Minichiello, L., Korte, M., Wolfer, D., Kühn, R., Unsicker, K., Cestari, V., et al. (1999). Essential role for TrkB receptors in hippocampus-mediated learning. Neuron, 24, 401–414.PubMedCrossRef
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(5), 292–295.PubMedCrossRef
Mizoguchi, H., Nakade, J., Tachibana, M., Ibi, D., Someya, E., Koike, H., et al. (2011). Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. Journal of Neuroscience, 31(36), 12963–12971.PubMedCrossRef
Molloy, C. A., Morrow, A. L., Meinzen-Derr, J., Schleifer, K., Dienger, K., Manning-Courtney, P., et al. (2006). Elevated cytokine levels in children with autism spectrum disorder. Journal Neuroimmunology, 172, 198–205.CrossRef
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.PubMedCrossRef
Murphy, A. C., Lalor, S. J., Lynch, M. A., & Mills, K. H. (2010). Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain, Behavior, and Immunity, 24(4), 641–651.PubMedCrossRef
Nimmerjanhn, A., Kirchhoff, F., & Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308, 1314–1318.CrossRef
Nishimura, K., Nakamura, K., Anitha, A., Yamada, K., Tsujii, M., Iwayama, Y., et al. (2007). Genetic analyses of the brain-derived neurotrophic factor (BDNF) gene in autism. Biochemical Biophysical Research Communications, 356(1), 200–206.PubMedCrossRef
Onore, C., Enstrom, A., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Van de Water, J., et al. (2009). Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders. Journal of Neuroimmunology, 216(1–2), 126–129.PubMedPubMedCentralCrossRef
Pang, P. T., Teng, H. K., Zaitsev, E., Woo, N. T., Sakata, K., Zhen, S., et al. (2004). Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science, 306(5695), 487–491.PubMedCrossRef
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, 71, 656–662.
Parkhurst, C. N., Yang, G., Ninan, I., Savas, J. N., Yates, J. R., Lafgaille, J. J., et al. (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell, 155, 1596–1609.PubMedPubMedCentralCrossRef
Persico, T., & Bourgeron, T. (2006). Searching for ways out of the autism maze: Genetic, epigenetic and environmental clues. Trends in Neuroscience, 29, 349–358.CrossRef
Polleux, F., & Lauder, J. M. (2004). Towards a Developmental Neurobiology of Autism. Mental Retardation and Developmental Disabilities Research Reviews, 10(4), 303–317.PubMedCrossRef
Prakash, N., Cohen-Cory, S., & Frostig, R. (1996). Rapid and opposite effects of BDNF and NGF on the functional organization of the adult cortex in vivo. Nature, 381, 702–706.PubMedCrossRef
Quattrocchi, C. C., Wannenes, F., Persico, A. M., Ciafre, S. A., D’argengelo, G., Farace, M. G., et al. (2002). Reelin is a serine protease of the extracellular matrix. Journal of Biological Chemistry, 277, 303–309.PubMedCrossRef
Ransohoff, R. M., & Perry, V. H. (2009). Microglial physiology: Unique stimuli, specialized responses. Annual Review of Immunology, 27, 119–145.PubMedCrossRef
Rauskolb, S., Zagrebelsky, M., Dreznjak, A., Deogracias, R., Matsumoto, T., Wiese, S., et al. (2010). Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth. Journal of Neuroscience, 30(5), 1739–1749.PubMedCrossRef
Raznahan, A., Toro, R., Proitsi, P., Powell, J., Paus, T., Bolton, P. F., et al. (2009). A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder. Journal of Neurodevelopmental Disorders, 1(3), 215–223.PubMedPubMedCentralCrossRef
Rodier, P. M., Ingram, J. L., Tisdale, B., Nelson, S., & Romano, J. (1996). Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei. Journal of Comparative Neurology, 370(2), 247–261.PubMedCrossRef
Romagnani, S. (1997). Atopic allergy and other hypersensitivities interactions between genetic susceptibility, innocuous and microbial antigens and the immune system. Current Opinion in Immunology, 9, 773–775.PubMedCrossRef
Roux, P. P., & Barker, P. A. (2002). Neurotrophin signaling through the p75 neurotrophin receptor. Progress in Neurobiology, 67(3), 203–233.PubMedCrossRef
Sato, A., Kasai, S., Kobayashi, T., Takamatsu, Y., Hino, O., Ikeda, K., et al. (2012). Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nature Communications, 3, 1292.PubMedPubMedCentralCrossRef
Scearce-Levie, K., Roberson, E. D., Gerstein, H., Cholfin, J. A., Mandiyan, V. S., Shah, N. M., et al. (2008). Abnormal social behaviors in mice lacking Fgf17. Genes Brain and Behavior, 7(3), 344–354.CrossRef
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., et al. (2012). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 74, 691–705.PubMedPubMedCentralCrossRef
Schafer, D. P., Lehrman, E. K., & Stevens, B. (2013). The “quad-partite” synapse: Microglia-synapse interactions in the developing and mature CNS. Glia, 61, 24–36.PubMedCrossRef
Schmid, D. A., Yang, T., Ogier, M., Adams, I., Mirakhur, Y., Wang, Q., et al. (2012). A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. Journal of Neuroscience, 32, 1803–1810.PubMedPubMedCentralCrossRef
Seidah, N. G., Benjannet, S., Pareek, S., Chrétien, M., & Murphy, R. A. (1996). Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Letters, 379(3), 247–250.PubMedCrossRef
Shatz, C. J. (1990). Impulse activity and the patterning of connections during CNS development. Neuron, 5, 745–756.PubMedCrossRef
Sheikh, A. M., Malik, M., Wen, G., Chauhan, A., Chauhan, V., Gong, C. X., et al. (2010). BDNFAkt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. Journal of Neuroscience Research, 88, 2641–2647.PubMed
Sometani, A., Kataoka, H., Nitta, A., Fukumitsu, H., Nomoto, H., & Furukawa, S. (2001). Transforming growth factor-beta1 enhances expression of brain-derived neurotrophic factor and its receptor, TrkB, in neurons cultured from rat cerebral cortex. Journal of Neuroscience Research, 66(3), 369–376.PubMedCrossRef
Stephan, A. H., Barres, B. A., & Stevens, B. (2012). The complement system: An unexpected role in synaptic pruning during development and disease. Annual Review in Neuroscience, 35, 369–389.CrossRef
Stromland, K., Nordin, V., Miller, M., et al. (1994). Autism in thalidomide embryopathy: A population study. Developmental Medicine and Child Neurology, 36(4), 351–356.PubMedCrossRef
Sun, Y., Lim, Y., Li, F., Liu, S., Lu, J. J., Haberberger, R., et al. (2012). ProBDNF collapses neurite outgrowth of primary neurons by activating RhoA. PLoS ONE, 7(4), e35883.PubMedPubMedCentralCrossRef
Sutton, C., Brereton, C., Keogh, B., Mills, K. H. G., & Lavelle, E. C. (2006). A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. Journal of Experimental Medicine, 203, 1685–1691.PubMedPubMedCentralCrossRef
Tanako, T. (2015). Role of microglia in Autism: Recent advances. Developmental Neuroscience, 37, 195–202.CrossRef
Tong, L., Prieto, G. A., Kramár, E. A., Smith, E. D., Cribbs, D. H., Lynch, G., et al. (2012). Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1β via p38 mitogen-activated protein kinase. Journal of Neuroscience, 32(49), 17714–17724.PubMedPubMedCentralCrossRef
Tropea, D., Giacometti, E., Wilson, N. R., Beard, C., McCurry, C., Fu, D. D., et al. (2009). Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proceedings of the National Academy of Sciences USA, 106(6), 2029–2034.CrossRef
Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., & Pardo, C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology, 57(1), 67–81.PubMedCrossRef
Vyssotski, A. L., Dell’Omo, G., Poletaeva, I. I., Vyssotsk, D. L., Minichiello, L., Klein, R., et al. (2002). Long-term monitoring of hippocampus-dependent behavior in naturalistic settings: Mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility. Hippocampus, 12(1), 27–38.PubMedCrossRef
Wetmore, C., Ernfors, P., Persson, H., & Olson, L. (1990). Localization of brain-derived neurotrophic factor mRNA in neurons in the brain by in situ hybridization. Experimental Neurology, 109, 141–152.PubMedCrossRef
Wetsel, W. C., Rodriguiz, R. M., Guillemot, J., Rousselet, E., Essalmani, R., Kim, I. H., et al. (2013). Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice. Proceedings of the National Academy of Sciences USA, 110(43), 17362–17367.CrossRef
Wong, J., & Garner, B. (2012). Evidence that truncated TrkB isoform, TrkB-Shc can regulate phosphorylated TrkB protein levels. Biochemical and Biophysical Research Communications, 420(2), 331–335.PubMedCrossRef
Wong, Y. H., Lee, C. M., Xie, W., Cui, B., & Poo, M. M. (2015). Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin. Proceedings of the National Academy of Sciences USA, 112(32), E4475–E4484.CrossRef
Xie, L., Choudhury, G. R., Winters, A., Yang, S. H., & Jin, K. (2015). Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. European Journal of Immunology, 45(1), 180–191.PubMedCrossRef
Yang, L., Anderson, D. E., Baecher-Allan, C., Hastings, W. D., Bettelli, E., Oukka, M., et al. (2008). IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature, 454(7202), 350–352.PubMedPubMedCentralCrossRef
Yang, F., Je, H. S., Ji, Y., Nagappan, G., Heamstead, B., & Lu, B. (2009). Pro-BDNF-induced synaptic depression and retraction at developing neuromuscular synapses. Journal of Cell Biology, 185, 727–741.PubMedPubMedCentralCrossRef
Yi, H., Hu, J., Qian, J., & Hackam, A. S. (2012). Expression of brain-derived neurotrophic factor (BDNF) is regulated by the Wnt signaling pathway. NeuroReport, 23(3), 189–194.PubMedPubMedCentralCrossRef
Yoshii, A., & Constantine-Paton, M. (2010). Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Developmental Neurobiology, 70(5), 304–322.PubMedPubMedCentral
Zhan, Y., Paolicelli, R. C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F., et al. (2014). Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nature Neuroscience, 17, 400–406.PubMedCrossRef
Zhou, J., Blundell, J., Ogawa, S., Kwon, C. H., Zhang, W., Sinton, C., et al. (2009). Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. Journal of Neuroscience, 29(6), 1773–1783.PubMedPubMedCentralCrossRef
Zimmerman, A. W., Jyonouchi, H., Comi, A. M., Connors, S. L., Milstien, S., Varsou, A., et al. (2005). Cerebrospinal fluid and serum markers of inflammation in autism. Pediatric Neurology, 33, 195–201.PubMedCrossRef
Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Grinberg, N., et al. (2006). Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neuroscience, 9, 268–275.PubMedCrossRef
Ziv, Y., & Schwartz, M. (2008). Immune-based regulation of adult neurogenesis: Implications for learning and memory. Brain, Behavior, and Immunity, 22, 167–176.PubMedCrossRef
Zörner, B., Wolfer, D. P., Brandis, D., Kretz, O., Zacher, C., Madani, R., et al. (2003). Forebrain-specific trkB-receptor knockout mice: Behaviorally more hyperactive than “depressive”. Biological Psychiatry, 54(10), 972–982.PubMedCrossRef
Metadata
Title
Neuroimmunologic and Neurotrophic Interactions in Autism Spectrum Disorders: Relationship to Neuroinflammation
Authors
Kshama Ohja
Evelyne Gozal
Margaret Fahnestock
Lu Cai
Jun Cai
Jonathan H. Freedman
Andy Switala
Ayman El-Baz
Gregory Neal Barnes
Publication date
01-06-2018
Publisher
Springer US
Published in
NeuroMolecular Medicine / Issue 2/2018
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI
https://doi.org/10.1007/s12017-018-8488-8

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