Gastrointestinal symptoms and altered blood phospholipid profiles have been reported in patients with autism spectrum disorders (ASD). Most of the phospholipid analyses have been conducted on the fatty acid composition of isolated phospholipid classes following hydrolysis. A paucity of information exists on how the intact phospholipid molecular species are altered in ASD. We applied ESI/MS to determine how brain and blood intact phospholipid species were altered during the induction of ASD-like behaviors in rats following intraventricular infusions with the enteric bacterial metabolite propionic acid. Animals were infused daily for 8 days, locomotor activity assessed, and animals killed during the induced behaviors. Propionic acid infusions increased locomotor activity. Lipid analysis revealed treatment altered 21 brain and 30 blood phospholipid molecular species. Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species. These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.

Autism spectrum disorder (ASD) is a family of neurodevelopmental disorders characterized by restrictive interests, repetitive behaviors, deficits in social understanding and interactions, impairments in language development and communications skills. Associated symptoms also include self-injurious behavior, aggression and epilepsy (Amminger et al. 2007). During the last decade, ASD cases in North America indicate a dramatic increase with a prevalence of Received October 21, 2009; revised manuscript received January 18, 2010; Accepted January 19, 2010. Address correspondence and reprint requests to Dr Derrick MacFabe, Kilee Patchell-Evans Autism Research Group, The University of Western Ontario, London, Ontario, Canada N6A 5C2. E-mail: dmacfabe@uwo.caAbbreviations used: ASD, autism spectrum disorder; BUT, butyric acid; CL, cardiolipin; DMA, dimethyl acetal; ESI-MS, electrospray ionization mass spectrometry; FAME, fatty acid methyl ester; FID, flame ionization detection; GC/MS, gas chromatography/mass spectrometry; ICV, intracerebroventricular; PBS, phosphate-buffered saline; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PPA, propionic acid; PS, phosphatidylserine; PUFA, polyunsaturated fatty acids; SM, sphingomyelin. AbstractRecent studies have demonstrated intraventricular infusions of propionic acid (PPA) a dietary and enteric short-chain fatty acid can produce brain and behavioral changes similar to those observed in autism spectrum disorder (ASD). The effects of PPA were further evaluated to determine if there are any alterations in brain lipids associated with the ASD-like behavioral changes observed following intermittent intraventricular infusions of PPA, the related enteric metabolite butyric acid (BUT) or phosphate-buffered saline vehicle. Both PPA and BUT produced significant increases (p < 0.001) in locomotor activity (total distance travelled and stereotypy). PPA and to a lesser extent BUT infusions decreased the levels of total monounsaturates, total x6 fatty acids, total phosphatidylethanolamine plasmalogens, the ratio of x6 : x3 and elevated the levels of total saturates in separated phospholipid species. In addition, total acylcarnitines, total longchain (C12-C24) acylcarnitines, total short-chain (C2 to C9) acylcarnitines, and the ratio of bound to free carnitine were increased following infusions with PPA and BUT. These results provide evidence of a relationship between changes in brain lipid profiles and the occurrence of ASD-like behaviors using the autism rodent model. We propose that altered brain fatty acid metabolism may contribute to ASD. Keywords: carnitine, clostridia, gap junctions, lipids, mitochondria, movement disorder, short-chain fatty acids. one in every 150 children under the age of 5 years (Bertrand et al. 2001;Herbert et al. 2006). Evidence exists for a strong genetic contribution to ASD. However, the lack of complete concordance as well as variances in the severity of autism in monozygotic twins (Hu et al. 2006) indicate that the recent ...

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