Skip to main content Accessibility help

Evidence of microglial activation in autism and its possible role in brain underconnectivity

  • Juan I. Rodriguez (a1) and Janet K. Kern (a1) (a2) (a3)


Evidence indicates that children with autism spectrum disorder (ASD) suffer from an ongoing neuroinflammatory process in different regions of the brain involving microglial activation. When microglia remain activated for an extended period, the production of mediators is sustained longer than usual and this increase in mediators contributes to loss of synaptic connections and neuronal cell death. Microglial activation can then result in a loss of connections or underconnectivity. Underconnectivity is reported in many studies in autism. One way to control neuroinflammation is to reduce or inhibit microglial activation. It is plausible that by reducing brain inflammation and microglial activation, the neurodestructive effects of chronic inflammation could be reduced and allow for improved developmental outcomes. Future studies that examine treatments that may reduce microglial activation and neuroinflammation, and ultimately help to mitigate symptoms in ASD, are warranted.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Evidence of microglial activation in autism and its possible role in brain underconnectivity
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Evidence of microglial activation in autism and its possible role in brain underconnectivity
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Evidence of microglial activation in autism and its possible role in brain underconnectivity
      Available formats


The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence . The written permission of Cambridge University Press must be obtained for commercial re-use.

Corresponding author

Correspondence should be addressed to: Janet K. Kern, Institute of Chronic Illnesses Inc., 408 North Allen Drive, Allen, TX 75013, USA phone: (214)592-6600 fax: 1(888)SCIA-123 or 1(888)724-2123 email:


Hide All
Adams, J.B., Johansen, L.J., Powell, L.D., Quig, D. and Rubin, R.A. (2011) Gastrointestinal flora and gastrointestinal status in children with autism – comparisons to typical children and correlation with autism severity. BMC Gastroenterology 11, 22.
Ahlsen, G., Rosengren, L., Belfrage, M., Palm, A., Haglid, K., Hamberger, A. et al. (1993) Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. Biological Psychiatry 33, 734743.
Al-Yafee, Y.A., Al-Ayadhi, L.Y., Haq, S.H. and El-Ansary, A.K. (2011) Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. BMC Neurology 11, 139.
Ashutosh, K. (2000) Nitric oxide and asthma: a review. Current Opinion in Pulmonary Medicine 6, 2125.
Atladóttir, H.O., Thorsen, P., Schendel, D.E., Østergaard, L., Lemcke, S. and Parner, E.T. (2010) Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study. Archives of Pediatric and Adolescent Medicine 164, 470477.
Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M. et al. (1998) A clinicopathological study of autism. Brain 121, 889905.
Barttfeld, P., Wicker, B., Cukier, S., Navarta, S., Lew, S. and Sigman, M. (2011) A big-world network in ASD: dynamical connectivity analysis reflects a deficit in long-range connections and an excess of short-range connections. Neuropsychologia 49, 254263.
Belmonte, M.K., Allen, G., Beckel-Mitchener, A., Boulanger, L.M., Carper, R.A. and Webb, S.J. (2004) Autism and abnormal development of brain connectivity. Journal of Neuroscience 24, 92289231.
Boger-Megiddo, I., Shaw, D.W., Friedman, S.D., Sparks, B.F., Artru, A.A., Giedd, J.N. et al. (2006) Corpus callosum morphometrics in young children with autism spectrum disorder. Journal of Autism Developmental Disorders 36, 733739.
Bolaños, J.P., Heales, S.J., Land, J.M. and Clark, J.B. (1995) Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurones and astrocytes in primary culture. Journal of Neurochemistry 64, 19651972.
Brown, G.C. (2001) Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochimica et Biophysica Acta 1504, 4657.
Burroni, L., Orsi, A., Monti, L., Hayek, Y., Rocchi, R. and Vattimo, A.G. (2008) Regional cerebral blood flow in childhood autism: a SPET study with SPM evaluation. Nuclear Medicine Communications 29, 150156.
Calatayud, S., Barrachina, D. and Esplugues, J.V. (2001) Nitric oxide: relation to integrity, injury, and healing of the gastric mucosa. Microscopy Research and Technique 53, 325335.
Chatterjee, S., Noack, H., Possel, H. and Wolf, G. (2000) Induction of nitric oxide synthesis lowers intracellular glutathione in microglia of primary glial cultures. Glia 29, 98101.
Chauhan, A., Audhya, T. and Chauhan, V. (2012) Brain region-specific glutathione redox imbalance in autism. Neurochemical Research (Epub ahead of print).
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, 361365.
Colton, C.A. and Gilbert, D.L. (1987) Production of superoxide anions by a CNS macrophage, the microglia. FEBS Letters 223, 284288.
Courchesne, E. (1997) Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Current Opinion in Neurobiology 7, 269278.
Courchesne, E. and Pierce, K. (2002) Autism. In Ramachandran, V.S. (ed) Encyclopedia of the Human Brain. Academic, San Diego, pp. 321342.
Damarla, S.R., Keller, T.A., Kana, R.K., Cherkassky, V.L., Williams, D.L., Minshew, N.J. et al. (2010) Cortical underconnectivity coupled with preserved visuospatial cognition in autism: evidence from an fMRI study of an embedded figures task. Autism Research 3, 273279.
Danielsson, S., Gillberg, I.C., Billstedt, E., Gillberg, C. and Olsson, I. (2005) Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia 46, 918923.
Devenney, I., Norrman, G., Forslund, T., Fälth-Magnusson, K. and Sundqvist, T. (2010) Urinary nitric oxide excretion in infants with eczema. Pediatric Allergy and Immunology 21, e229e234.
Dijkstra, G., van Goor, H., Jansen, P.L. and Moshage, H. (2004) Targeting nitric oxide in the gastrointestinal tract. Current Opinion in Investigational Drugs 5, 529536.
Di Martino, A., Kelly, C., Grzadzinski, R., Zuo, X.N., Mennes, M., Mairena, M.A. et al. (2011) Aberrant striatal functional connectivity in children with autism. Biological Psychiatry 69, 847856.
Ebisch, S.J., Gallese, V., Willems, R.M., Mantini, D., Groen, W.B., Romani, G.L. et al. (2011) Altered intrinsic functional connectivity of anterior and posterior insula regions in high-functioning participants with autism spectrum disorder. Human Brain Mapping 32, 10131028.
Enstrom, A.M., Lit, L., Onore, C.E., Gregg, J.P., Hansen, R.L., Pessah, I.N. et al. (2005) Immunity, neuroglia and neuroinflammation in autism. International Review of Psychiatry 17, 485495.
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, 124133.
Fatemi, S.H., Folsom, T.D., Reutiman, T.J. and Lee, S. (2008) Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism. Synapse 62, 501507.
Gehrmann, J., Matsumoto, Y. and Kreutzberg, G.W. (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Research Reviews 20, 269287.
Geier, D.A., Kern, J.K., Garver, C.R., Adams, J.B., Audhya, T. and Geier, M.R. (2009) A prospective study of transsulfuration biomarkers in autistic disorders. Neurochemical Research 34, 386393.
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, 23892396.
Heales, S.J., Bolaños, J.P. and Clark, J.B. (1996) Glutathione depletion is accompanied by increased neuronal nitric oxide synthase activity. Neurochemical Research 21, 3539.
Herbert, M.R. (2005) Large brains in autism: the challenge of pervasive abnormality. Neuroscientist 11, 417440.
Herbert, M.R., Ziegler, D.A., Deutsch, C.K., O'Brien, L.M., Kennedy, D.N., Filipek, P.A. et al. (2005) Brain asymmetries in autism and developmental language disorder: a nested whole-brain analysis. Brain 128, 213226.
Herbert, M.R., Ziegler, D.A., Makris, N., Filipek, P.A., Kemper, T.L., Normandin, J.J. et al. (2004) Localization of white matter volume increase in autism and developmental language disorder. Annals of Neurology 55, 530540.
Hirrlinger, J., Gutterer, J.M., Kussmaul, L., Hamprecht, B. and Dringen, R. (2000) Microglial cells in culture express a prominent glutathione system for the defense against reactive oxygen species. Developmental Neuroscience 22, 384392.
James, S.J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D.W. et al. (2004) Metabolic biomarkers of oxidative stress and impaired methylation capacity in children with autism. American Journal of Clinical Nutrition 80, 16111617.
James, S.J., Melnyk, S., Jernigan, S., Cleves, M.A., Halsted, C.H., Wong, D.H. et al. (2006) Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics 141B, 947956.
James, S.J., Rose, S., Melnyk, S., Jernigan, S., Blossom, S., Pavliv, O. et al. (2009) Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB Journal 23, 23742383.
Just, M.A., Cherkassky, V.L., Keller, T.A., Kana, R.K. and Minshew, N.J. (2007) Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry. Cerebellar Cortex 17, 951961.
Kagan-Kushnir, T., Roberts, S.W. and Snead, O.C. III (2005) Screening electroencephalograms in autism spectrum disorders: evidence-based guideline. Journal of Child Neurology 20, 197206.
Kana, R.K., Keller, T.A. and Cherkassky, V.L. (2009) Atypical frontal-posterior synchronization of Theory of Mind regions in autism during mental state attribution. Society Neuroscience 4, 135152.
Kann, O., Kovács, R., Njunting, M., Behrens, C.J., Otáhal, J., Lehmann, T.N. et al. (2005) Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans. Brain 128, 23962407.
Kigerl, K.A., Ankeny, D.P., Garg, S.K., Wei, P., Guan, Z., Lai, W. et al. (2011) System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo. Experimental Neurology 233, 333341.
Kovács, R., Rabanus, A., Otáhal, J., Patzak, A., Kardos, J., Albus, K. et al. (2009) Endogenous nitric oxide is a key promoting factor for initiation of seizure-like events in hippocampal and entorhinal cortex slices. Journal of Neuroscience 29, 85658577.
Kunz, W.S., Kudin, A.P., Vielhaber, S., Blümcke, I., Zuschratter, W., Schramm, J. et al. (2000) Mitochondrial complex I deficiency in the epileptic focus of patients with temporal lobe epilepsy. Annals of Neurology 48, 766773.
Laurence, J.A. and Fatemi, S.H. (2005) Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum 4, 206210.
Lee, R.H., Mills, E.A., Schwartz, N., Bell, M.R., Deeg, K.E., Ruthazer, E.S. et al. (2010) Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system. Neural Development 5, 2.
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, 111116.
Maenner, M.J., Arneson, C.L., Levy, S.E., Kirby, R.S., Nicholas, J.S. and Durkin, M.S. (2011) Brief report: association between behavioral features and gastrointestinal problems among children with autism spectrum disorder. Journal of Autism and Developmental Disorders [Epub ahead of print]
Minshew, N.J. and Keller, T.A. (2010) The nature of brain dysfunction in autism: functional brain imaging studies. Current Opinion in Neurology 23, 124130.
Monnet-Tschudi, F., Defaux, A., Braissant, O., Cagnon, L. and Zurich, M.G. (2011) Methods to assess neuroinflammation. Current Protocols in Toxicology, Chapter 12, Unit 12.19.
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, 368376.
Moss, D.W. and Bates, T.E. (2001) Activation of murine microglial cell lines by lipopolysaccharide and interferon-γ causes NO-mediated decreases in mitochondrial and cellular function. European Journal of Neuroscience 13, 529538.
Naik, U.S., Gangadharan, C., Abbagani, K., Nagalla, B., Dasari, N. and Manna, S.K. (2011) A study of nuclear transcription factor-kappa B in childhood autism. PLoS One 6, e19488.
Nakanishi, H., Hayashi, Y. and Wu, Z. (2011) The role of microglial mtDNA damage in age-dependent prolonged LPS-induced sickness behavior. Neuron Glia Biology 28, 17.
Nicolson, G.L., Gan, R., Nicolson, N.L. and Haier, J. (2007) Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. Journal of Neuroscience Research 85, 11431148.
Palmen, S.J., van Engeland, H., Hof, P.R. and Schmitz, C. (2004) Neuropathological findings in autism. Brain 127, 25722583.
Pardo, C.A., Vargas, D.L. and Zimmerman, A.W. (2005) Immunity, neuroglia and neuroinflammation in autism. International Review of Psychiatry 17, 485495.
Radewicz, K., Garey, L.J., Gentleman, S.M. and Reynolds, R. (2000) Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. Journal of Neuropathology and Experimental Neurology 59, 137150.
Reinders, C.I., Herulf, M., Ljung, T., Hollenberg, J., Weitzberg, E., Lundberg, J.O. et al. (2005) Rectal mucosal nitric oxide in differentiation of inflammatory bowel disease and irritable bowel syndrome. Clinical Gastroenterology and Hepatology 3, 777783.
Rintoul, G.L., Bennett, V.J., Papaconstandinou, N.A. and Reynolds, I.J. (2006) Nitric oxide inhibits mitochondrial movement in forebrain neurons associated with disruption of mitochondrial membrane potential. Journal of Neurochemistry 97, 800806.
Rosengren, L.E., Ahlsén, G., Belfrage, M., Gillberg, C., Haglid, K.G. and Hamberger, A. (1992) A sensitive ELISA for glial fibrillary acidic protein: application in CSF of children. Journal of Neuroscience Methods 44, 113119.
Schieve, L.A., Gonzalez, V., Boulet, S.L., Visser, S.N., Rice, C.E., Braun, K.V. et al. (2011) Concurrent medical conditions and health care use and needs among children with learning and behavioral developmental disabilities, National Health Interview Survey, 2006–2010. Research in Developmental Disabilities 33, 467476.
Shukla, D.K., Keehn, B., Lincoln, A.J. and Müller, R.A. (2010) White matter compromise of callosal and subcortical fiber tracts in children with autism spectrum disorder: a diffusion tensor imaging study. Journal of the American Academy of Child & Adolescent Psychiatry 49, 12691278.
Somera-Molina, K.C., Nair, S., Van Eldik, L.J., Watterson, D.M. and Wainwright, M.S. (2009) Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a ‘two-hit’ seizure model. Brain Research 1282, 162172.
Somera-Molina, K.C., Robin, B., Somera, C.A., Anderson, C., Stine, C., Koh, S. et al. (2007) Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation. Epilepsia 48, 17851800.
Stewart, V.C. and Heales, S.J. (2003) Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration. Free Radical Biology and Medicine 34, 287303.
Streit, W.J., Mrak, R.E. and Griffin, W.S. (2004) Microglia and neuroinflammation: a pathological perspective. Journal of Neuroinflammation 1, 14.
Streita, W.J. (2006) Microglial senescence: does the brain's immune system have an expiration date? Trends in Neuroscience 29, 506510.
Takabayashi, A., Kawai, Y., Iwata, S., Kanai, M., Denno, R., Kawada, K. et al. (2000) Nitric oxide induces a decrease in the mitochondrial membrane potential of peripheral blood lymphocytes, especially in natural killer cells. Antioxidants and Redox Signaling 2, 673680.
Tang, B., Piazza, C.C., Dolezal, D. and Stein, M.T. (2011) Severe feeding disorder and malnutrition in 2 children with autism. Journal of Developmental and Behavioral Pediatrics 32, 264267.
Tetreault, N.A., Hakeem, A.Y., Jiang, S., Williams, B.A., Allman, E., Wold, B.J. et al. (2012) Microglia in the cerebral cortex in autism. Journal of Autism and Developmental Disorders [Epub ahead of print].
Toda, N., Ayajiki, K. and Okamura, T. (2009) Cerebral blood flow regulation by nitric oxide in neurological disorders. Canadian Journal of Physiology and Pharmacology 87, 581594.
Valko, M., Leibfritz, D., Moncol, J., Cronin, M.T., Mazur, M. and Telser, J. (2007) Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry and Cell Biology 39, 4484.
Vannacci, A., Ravaldi, C., Giannini, L., Rotella, C.M., Masini, E., Faravelli, C. et al. (2006) Increased nitric oxide production in eating disorders. Neuroscience Letters 399, 230233.
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, 304.
Vojdani, A., Mumper, E., Granpeesheh, D., Mielke, L., Traver, D., Bock, K. et al. (2008) Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15. Journal of Neuroimmunology 205, 148154.
Wang, L.W., Tancredi, D.J. and Thomas, D.W. (2011) The prevalence of gastrointestinal problems in children across the United States with autism spectrum disorders from families with multiple affected members. Journal of Developmental and Behavioral Pediatrics 32, 351360.
Wass, S. (2011) Distortions and disconnections: disrupted brain connectivity in autism. Brain Cognition 75, 1828.
Wood, P.L. (2003) Roles of CNS macrophages in neurodegeneration. In Neuroinflammation. Mechanisms and Management, 2nd edition. Wood, P.L. (ed.). Humana Press, Totowa, NJ, pp. 327.
Yates, D.H. (2001) Role of exhaled nitric oxide in asthma. Immunology and Cell Biology 79, 178190.
Young, A.M., Campbell, E., Lynch, S., Suckling, J. and Powis, S.J. (2011) Aberrant NF-kappaB expression in autism spectrum condition: a mechanism for neuroinflammation. Frontiers in Psychiatry 2, 27.
Yuan, H., Gerencser, A.A., Liot, G., Lipton, S.A., Ellisman, M., Perkins, G.A. et al. (2007) Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death and Differentiation 14, 462471.
Zimmerman, A.W., Jyonouchi, H., Comi, A.M., Connors, S.L., Milstein, S., Varsou, A. et al. (2005) Cerebrospinal fluid and serum markers of inflammation in autism. Pediatric Neurology 33, 195201.


Related content

Powered by UNSILO

Evidence of microglial activation in autism and its possible role in brain underconnectivity

  • Juan I. Rodriguez (a1) and Janet K. Kern (a1) (a2) (a3)


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.