Advertisement

Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism

      Background

      In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates.

      Methods

      Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator.

      Results

      Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure.

      Conclusions

      The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations.

      Key Words

      To read this article in full you will need to make a payment
      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pardo C.A.
        • Vargas D.L.
        • Zimmerman A.W.
        Immunity, neuroglia and neuroinflammation in autism.
        Int Rev Psychiatry. 2005; 17: 485-495
        • Ashwood P.
        • Wills S.
        • Van de Water J.
        The immune response in autism: A new frontier for autism research.
        J Leukoc Biol. 2006; 80: 1-15
        • Singh V.K.
        • Warren R.P.
        • Odell J.D.
        • Cole P.
        Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children.
        Clin Immunol Immunopathol. 1991; 61: 448-455
        • Ahlsen 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
        • Gupta S.
        • Aggarwal S.
        • Rashanravan B.
        • Lee T.
        Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism.
        J Neuroimmunol. 1998; 85: 106-109
        • 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
        • Vargas D.L.
        • Nascimbene C.
        • Krishnan C.
        • Zimmerman A.W.
        • Pardo C.A.
        Neuroglial activation and neuroinflammation in the brain of patients with autism.
        Ann Neurol. 2005; 57: 67-81
        • Zimmerman A.W.
        • Jyonouchi H.
        • Comi A.M.
        • Connors S.L.
        • Milstien S.
        • Varsou A.
        • Heyes M.P.
        Cerebrospinal fluid and serum markers of inflammation in autism.
        Pediatr Neurol. 2005; 33: 195-201
        • Laurence J.A.
        • Fatemi S.H.
        Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects.
        Cerebellum. 2005; 4: 206-210
        • Garbett K.
        • Ebert P.J.
        • Mitchell A.
        • Lintas C.
        • Manzi B.
        • Mirnics K.
        • Persico A.M.
        Immune transcriptome alterations in the temporal cortex of subjects with autism.
        Neurobiol Dis. 2008; 30: 303-311
        • Li X.
        • Chauhan A.
        • Sheikh A.M.
        • Patil S.
        • Chauhan V.
        • Li X.M.
        • et al.
        Elevated immune response in the brain of autistic patients.
        J Neuroimmunol. 2009; 207: 111-116
        • Bailey A.
        • Luthert P.
        • Dean A.
        • Harding B.
        • Janota I.
        • Montgomery M.
        • et al.
        A clinicopathological study of autism.
        Brain. 1998; 121: 889-905
        • Ransohoff R.M.
        • Perry V.H.
        Microglial physiology: Unique stimuli, specialized responses.
        Annu Rev Immunol. 2009; 27: 119-145
        • Rezaie P.
        • Trillo-Pazos G.
        • Everall I.P.
        • Male D.K.
        Expression of beta-chemokines and chemokine receptors in human fetal astrocyte and microglial co-cultures: Potential role of chemokines in the developing CNS.
        Glia. 2002; 37: 64-75
        • Rezaie P.
        • Dean A.
        • Male D.
        • Ulfig N.
        Microglia in the cerebral wall of the human telencephalon at second trimester.
        Cereb Cortex. 2005; 15: 938-949
        • Chan W.Y.
        • Kohsaka S.
        • Rezaie P.
        The origin and cell lineage of microglia: New concepts.
        Brain Res Rev. 2007; 53: 344-354
        • Courchesne E.
        • Karns C.
        • Davis H.R.
        • Ziccardi R.
        • Carper R.
        • Tigue Z.
        • et al.
        Unusual brain growth patterns in early life in patients with autistic disorder: An MRI study.
        Neurology. 2001; 57: 245-254
        • Redcay E.
        • Courchesne E.
        When is the brain enlarged in autism?.
        Biol Psychiatry. 2005; 58: 1-9
        • Sparks B.F.
        • Friedman S.D.
        • Shaw D.W.
        • Aylward E.
        • Echelard D.
        • Artru A.A.
        • et al.
        Brain structural abnormalities in young children with autism spectrum disorder.
        Neurology. 2002; 59: 184-192
        • Boger-Megiddo I.
        • Shaw D.W.
        • Friedman S.D.
        • Sparks B.F.
        • Artru A.A.
        • Giedd J.N.
        • et al.
        Corpus callosum morphometrics in young children with autism spectrum disorder.
        J Autism Dev Disord. 2006; 36: 733-739
        • Dissanayake C.
        • Bui Q.M.
        • Huggins R.
        • Loesch D.Z.
        Growth in stature and head circumference in high-functioning autism and Asperger disorder during the first 3 years of life.
        Dev Psychopathol. 2006; 18: 381-393
        • Dementieva Y.A.
        • Vance D.D.
        • Donnelly S.L.
        • Elston L.A.
        • Wolpert C.M.
        • Ravan S.A.
        • et al.
        Accelerated head growth in early development of individuals with autism.
        Pediatr Neurol. 2005; 32: 102-108
        • Hazlett H.C.
        • Poe M.
        • Gerig G.
        • Smith R.G.
        • Provenzale J.
        • Ross A.
        • et al.
        Magnetic resonance imaging and head circumference study of brain size in autism: Birth through age 2 years.
        Arch Gen Psychiatry. 2005; 62: 1366-1376
        • Carper R.A.
        • Moses P.
        • Tigue Z.D.
        • Courchesne E.
        Cerebral lobes in autism: Early hyperplasia and abnormal age effects.
        Neuroimage. 2002; 16: 1038-1051
        • Carper R.A.
        • Courchesne E.
        Localized enlargement of the frontal cortex in early autism.
        Biol Psychiatry. 2005; 57: 126-133
        • Tuchman R.
        • Rapin I.
        Epilepsy in autism.
        Lancet Neurol. 2002; 1: 352-358
        • Imai Y.
        • Ibata I.
        • Ito D.
        • Ohsawa K.
        • Kohsaka S.
        A novel gene Iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage.
        Biochem Biophys Res Commun. 1996; 224: 855-862
        • Friedman W.J.
        Cytokines regulate expression of the type 1 interleukin-1 receptor in rat hippocampal neurons and glia.
        Exp Neurol. 2001; 168: 23-31
        • Del Rio-Hortega P.
        Microglia.
        in: Penfield W. Cytology and Cellular Pathology of the Nervous System. Hafner, New York1932: 483-584
        • Ito D.
        • Tanaka K.
        • Suzuki S.
        • Dembo T.
        • Fukuuchi Y.
        Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain.
        Stroke. 2001; 32: 1208-1215
        • Shi L.
        • Fatemi S.H.
        • Sidwell R.W.
        • Patterson P.H.
        Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring.
        J Neurosci. 2003; 23: 297-302
        • Patterson P.H.
        Maternal infection: Window on neuroimmune interactions in fetal brain development and mental illness.
        Curr Opin Neurobiol. 2002; 12: 115-118
        • Todd R.D.
        • Ciaranello R.D.
        Demonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child.
        Proc Natl Acad Sci U S A. 1985; 82: 612-616
        • Todd R.D.
        • Hickok J.M.
        • Anderson G.M.
        • Cohen D.J.
        Antibrain antibodies in infantile autism.
        Biol Psychiatry. 1988; 23: 644-647
        • Singh V.K.
        • Warren R.P.
        • Odell J.D.
        • Warren W.L.
        • Cole P.
        Antibodies to myelin basic protein in children with autistic behavior.
        Brain Behav Immun. 1993; 7: 97-103
        • Singh V.K.
        • Warren R.
        • Averett R.
        • Ghaziuddin M.
        Circulating autoantibodies to neuronal and glial filament proteins in autism.
        Pediatr Neurol. 1997; 17: 88-90
        • Connolly A.M.
        • Chez M.G.
        • Pestronk A.
        • Arnold S.T.
        • Mehta S.
        • Deuel R.K.
        Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders.
        J Pediatr. 1999; 134: 607-613
        • Ashwood P.
        • Van de Water J.
        A review of autism and the immune response.
        Clin Dev Immunol. 2004; 11: 165-174
        • Singh V.K.
        • Rivas W.H.
        Prevalence of serum antibodies to caudate nucleus in autistic children.
        Neurosci Lett. 2004; 355: 53-56
        • Connolly A.M.
        • Chez M.
        • Streif E.M.
        • Keeling R.M.
        • Golumbek P.T.
        • Kwon J.M.
        • et al.
        Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy.
        Biol Psychiatry. 2006; 59: 354-363
        • Singer H.S.
        • Morris C.M.
        • Williams P.N.
        • Yoon D.Y.
        • Hong J.J.
        • Zimmerman A.W.
        Antibrain antibodies in children with autism and their unaffected siblings.
        J Neuroimmunol. 2006; 178: 149-155
        • Cabanlit M.
        • Wills S.
        • Goines P.
        • Ashwood P.
        • Van de Water J.
        Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder.
        Ann N Y Acad Sci. 2007; 1107: 92-103
        • Singer H.S.
        • Morris C.M.
        • Gause C.D.
        • Gillin P.K.
        • Crawford S.
        • Zimmerman A.W.
        Antibodies against fetal brain in sera of mothers with autistic children.
        J Neuroimmunol. 2008; 194: 165-172
        • Braunschweig D.
        • Ashwood P.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.
        • Croen L.A.
        • et al.
        Autism: Maternally derived antibodies specific for fetal brain proteins.
        Neurotoxicology. 2008; 29: 226-231
        • Wills S.
        • Cabanlit M.
        • Bennett J.
        • Ashwood P.
        • Amaral D.G.
        • Van de Water J.
        Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders.
        Brain Behav Immun. 2009; 23: 64-74
        • Byram S.C.
        • Carson M.J.
        • DeBoy C.A.
        • Serpe C.J.
        • Sanders V.M.
        • Jones K.J.
        CD4-positive T cell-mediated neuroprotection requires dual compartment antigen presentation.
        J Neurosci. 2004; 24: 4333-4339
        • Rezaie P.
        • Dean A.
        Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system.
        Neuropathology. 2002; 22: 106-132
        • Rosenberg P.B.
        Clinical aspects of inflammation in Alzheimer's disease.
        Int Rev Psychiatry. 2005; 17: 503-514
        • Nagatsu T.
        • Sawada M.
        Cellular and molecular mechanisms of Parkinson's disease: Neurotoxins, causative genes, and inflammatory cytokines.
        Cell Mol Neurobiol. 2006; 26: 781-802
        • Heneka M.T.
        • O'Banion M.K.
        Inflammatory processes in Alzheimer's disease.
        J Neuroimmunol. 2007; 184: 69-91
        • Schumann C.M.
        • Amaral D.G.
        Stereological analysis of amygdala neuron number in autism.
        J Neurosci. 2006; 26: 7674-7679
        • van Kooten I.A.
        • Palmen S.J.
        • von Cappeln P.
        • Steinbusch H.W.
        • Korr H.
        • Heinsen H.
        • et al.
        Neurons in the fusiform gyrus are fewer and smaller in autism.
        Brain. 2008; 131: 987-999
        • Fatemi S.H.
        • Halt A.R.
        • Stary J.M.
        • Realmuto G.M.
        • Jalali-Mousavi M.
        Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum.
        Neuroreport. 2001; 12: 929-933
        • Fatemi S.H.
        • Halt A.R.
        Altered levels of Bcl2 and p53 proteins in parietal cortex reflect deranged apoptotic regulation in autism.
        Synapse. 2001; 42: 281-284
        • Araghi-Niknam M.
        • Fatemi S.H.
        Levels of Bcl-2 and P53 are altered in superior frontal and cerebellar cortices of autistic subjects.
        Cell Mol Neurobiol. 2003; 23: 945-952
        • Bauman M.
        • Kemper T.L.
        Histoanatomic observations of the brain in early infantile autism.
        Neurology. 1985; 35: 866-875
        • Bauman M.L.
        • Kemper T.L.
        Limbic and cerebellar abnormalities are also present in an autistic child of normal intelligence.
        Neurology. 1990; 40: 359
        • Kemper T.L.
        • Bauman M.L.
        The contribution of neuropathologic studies to the understanding of autism.
        Neurol Clin. 1993; 11: 175-187
        • Williams R.S.
        • Hauser S.L.
        • Purpura D.P.
        • DeLong G.R.
        • Swisher C.N.
        Autism and mental retardation: Neuropathologic studies performed in four retarded persons with autistic behavior.
        Arch Neurol. 1980; 37: 749-753
        • Ritvo E.R.
        • Freeman B.J.
        • Scheibel A.B.
        • Duong T.
        • Robinson H.
        • Guthrie D.
        • Ritvo A.
        Lower Purkinje cell counts in the cerebella of four autistic subjects: Initial findings of the UCLA-NSAC autopsy research report.
        Am J Psychiatry. 1986; 143: 862-866
        • Fehlow P.
        • Bernstein K.
        • Tennstedt A.
        • Walther F.
        Autismus infantum und exzessive aerophagie mit symptomatischem magakolon und ileus bei einem fall von Ehlers-Danlos-syndrom (Infantile autism and excessive aerophagy with symptomatic megacolon and ileus in a case of Ehlers-Danlos syndrome).
        Padiatr Grenzgeb. 1993; 31: 259-267
        • Courchesne E.
        Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism.
        Curr Opin Neurobiol. 1997; 7: 269-278
        • Marin-Teva J.L.
        • Dusart I.
        • Colin C.
        • Gervais A.
        • van Rooijen N.
        • Mallat M.
        Microglia promote the death of developing Purkinje cells.
        Neuron. 2004; 41: 535-547
        • Bessis A.
        • Bernard D.
        • Triller A.
        Tumor necrosis factor-alpha and neuronal development.
        Neuroscientist. 2005; 11: 277-281
        • Christopherson K.S.
        • Ullian E.M.
        • Stokes C.C.
        • Mullowney C.E.
        • Hell J.W.
        • Agah A.
        • et al.
        Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.
        Cell. 2005; 120: 421-433
        • Krenz N.R.
        • Weaver L.C.
        Nerve growth factor in glia and inflammatory cells of the injured rat spinal cord.
        J Neurochem. 2000; 74: 730-739
        • Batchelor P.E.
        • Liberatore G.T.
        • Wong J.Y.
        • Porritt M.J.
        • Frerichs F.
        • Donnan G.A.
        • Howells D.W.
        Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor.
        J Neurosci. 1999; 19: 1708-1716
        • Batchelor P.E.
        • Porritt M.J.
        • Martinello P.
        • Parish C.L.
        • Liberatore G.T.
        • Donnan G.A.
        • Howells D.W.
        Macrophages and microglia produce local trophic gradients that stimulate axonal sprouting toward but not beyond the wound edge.
        Mol Cell Neurosci. 2002; 21: 436-453