IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation

Abstract

BackgroundAlthough the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS) may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS.MethodsImmunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively.ResultsIn this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses.ConclusionsOur results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.

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“…There are information of decrease of the GABAergic system enzymes, elevated plasma GABA levels, and decreased availability of GABA in autistic patients. Lower GABA levels could reduce the threshold for rising seizures which are often linked with autism 11,51 .…”

“…The strongest evidence implicates the glutamatergic, GABAergic and serotonergic systems, with weaker evidence for cholinergic systems, catecholaminergic and peptidergic 37,38 . Most neurochemical ressearch on autism has focused on monoamines, although peptides, (amino acids, and metabolites, including y-aminobutyric acid (GABA) and excitatory amino acids, acetylcholine and other neuromodulators, may be implicated in the pathophysiology of autism 11,18,34 .…”

“…immune processes thought to contribute to the pathophysiology of autism [8][9][10][11] . These areas of study have contributed to the development of a number of medications in use for interfering the symptoms and may guide the upcoming development of novel agents 12 .…”

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“…Gene expression profiling [73,74] and biomarker studies find increases in cytokines in autistic subjects [75], particularly . These studies are consistent with findings of mitochondrial dysfunction and increased organellar fission in brain samples of autistic individuals [79].…”

Oxidative Stress and Dietary Interventions in Autism: Exploring the Role of Zinc, Antioxidant Enzymes and Other Micronutrients in the Neurobiology of Autism

“…These risk factors could be influenced by genetic mutations in genes involved in the inflammatory response such as TNF-alpha and interleukin 6 (IL-6) and in the maintenance of zinc homeostasis such as metallothioneins [34]. Il-6 has been associated with neurodegenerative disorders and autism [35,36]. In genetic studies, measurable differences associated with genes that encode enzymes and other proteins impacting the methylation cycle, the folate metabolism and the glutathione system are reported between children with autism and healthy controls [37].…”