Abstract
Autism spectrum condition (ASC) is recognized as having an inflammatory component. Post-mortem brain samples from patients with ASC display neuroglial activation and inflammatory markers in cerebrospinal fluid, although little is known about the underlying molecular mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements of NF-κB in human post-mortem samples of orbitofrontal cortex tissue donated to two independent centers: London Brain Bank, Kings College London, UK (ASC: n = 3, controls: n = 4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: n = 6, controls: n = 5). The hypothesis was that concentrations of NF-κB would be elevated, especially in activated microglia in ASC, and pH would be concomitantly reduced (i.e., acidification). Neurons, astrocytes, and microglia all demonstrated increased extranuclear and nuclear translocated NF-κB p65 expression in brain tissue from ASC donors relative to samples from matched controls. These between-groups differences were increased in astrocytes and microglia relative to neurons, but particularly pronounced for highly mature microglia. Measurement of pH in homogenized samples demonstrated a 0.98-unit difference in means and a strong (F = 98.3; p = 0.00018) linear relationship to the expression of nuclear translocated NF-κB in mature microglia. Acridine orange staining localized pH reductions to lysosomal compartments. In summary, NF-κB is aberrantly expressed in orbitofrontal cortex in patients with ASC, as part of a putative molecular cascade leading to inflammation, especially of resident immune cells in brain regions associated with the behavioral and clinical symptoms of ASC.
Highlights
Autism spectrum condition (ASC) is a life-long neurodevelopmental condition characterized by a triad of impairments in social skills, verbal communication, and behavior (Rapin, 1997; Lord et al, 2000)
There is evidence to suggest an association between ASC and neuroinflammation in anterior regions of the neocortex (Pardo et al, 2005; Vargas et al, 2005; Zimmerman et al, 2005), and areas relating to cognitive function appear to be affected by inflammation resulting from activation of microglia and astrocytes (Anderson et al, 2008)
For the first time to our knowledge, we report the aberrant expression of a pro-inflammatory transcription factor, NF-κB, in samples donated to the London Brain Bank (UK cohort) and Harvard Brain Tissue Resource Center (US cohort)
Summary
Autism spectrum condition (ASC) is a life-long neurodevelopmental condition characterized by a triad of impairments in social skills, verbal communication, and behavior (Rapin, 1997; Lord et al, 2000). In vivo measurements of structural brain changes with magnetic resonance imaging have detected gray matter loss in the orbitofrontal cortex (Hardan et al, 2006; Girgis et al, 2007) and impairment of cognitive functions mediated by the orbitofrontal–amygdala circuit (Loveland et al, 2008) in patients with ASC. Markers of oxidative stress are elevated in the orbitofrontal cortex in post-mortem samples of ASC patients (Sajdel-Sulkowska et al, 2011). This region is a likely candidate for an underlying cellular mechanism
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