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Saturday, May 17, 2008
Champagne Terrace/Bordeaux (Novotel London West)
Background: Diverse cell-cell interaction, neuroinflammatory and metabolic processes are implicated in the pathophysiology of autism spectrum disor ders (ASDs). Environmental agents may modulate these factors through epigenetic mechanisms. Propionic (PPA) or butyric acids (BA) are short chain fatty acids (SCFA) present in diet, and are also a product of enteric bacteria fermentation. SCFA have widespread effects on many of the above systems and may thus be a possible environmental trigger in ASD. We have shown that PPA can elicit consistent ASD related brain and behavioural changes in rodents, while BA can induce genes implicated in catecholamine, enkephalin and CREB related processes in vitro.
Objectives: To examine the effects of chronic intracerebroventricular infusions of SCFA on behaviour, neuropathology and gene expression in rats.
Methods: Adult rats received infusions of pH 7.5 buffered PPA or BA (.26M) or PBS vehicle (0.1M) twice daily for 7 treatment days. Immediately following microinfusion, the animals were individually placed into an automated open field (Versamax) and a variety of locomotor activity variables were assessed for 30 minutes.
After sacrifice brains were examined either neuropathologically for innate neuroinflammation, or via microarray analysis (Affymetrix Rat Genome GeneChip 230 2.0 microarrays/MetaCoreTM platform) for ASD related markers/genes.
Results: SCFA infusions increased locomotor activity. Both SCFA produced increased innate neuroinflammation(GFAP,IL-6) but only PPA produced activated microglia (CD68, IbA1). The alignment of gene content identified sets of genes unique for BA (274) and PPA (309). Comparison analyses of RNA identified a large number of genes (769) common for both groups, involved in canonical pathways/processes including cell development and differentiation, cytoskeleton organization and biogenesis, cell adhesion, inflammatory response, synaptic plasticity, cell-cell communication, neuroprotection and glutathione metabolism.
Conclusions: SCFA produce behavioural, neuropathological and gene expression effects reminiscent of ASD when intraventricularly infused in rats, providing further evidence of a plausible dietary/gut/CNS link to this disorder.
Objectives: To examine the effects of chronic intracerebroventricular infusions of SCFA on behaviour, neuropathology and gene expression in rats.
Methods: Adult rats received infusions of pH 7.5 buffered PPA or BA (.26M) or PBS vehicle (0.1M) twice daily for 7 treatment days. Immediately following microinfusion, the animals were individually placed into an automated open field (Versamax) and a variety of locomotor activity variables were assessed for 30 minutes.
After sacrifice brains were examined either neuropathologically for innate neuroinflammation, or via microarray analysis (Affymetrix Rat Genome GeneChip 230 2.0 microarrays/MetaCoreTM platform) for ASD related markers/genes.
Results: SCFA infusions increased locomotor activity. Both SCFA produced increased innate neuroinflammation(GFAP,IL-6) but only PPA produced activated microglia (CD68, IbA1). The alignment of gene content identified sets of genes unique for BA (274) and PPA (309). Comparison analyses of RNA identified a large number of genes (769) common for both groups, involved in canonical pathways/processes including cell development and differentiation, cytoskeleton organization and biogenesis, cell adhesion, inflammatory response, synaptic plasticity, cell-cell communication, neuroprotection and glutathione metabolism.
Conclusions: SCFA produce behavioural, neuropathological and gene expression effects reminiscent of ASD when intraventricularly infused in rats, providing further evidence of a plausible dietary/gut/CNS link to this disorder.