title: Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats.
abstract: Autism is a complex neurodevelopmental disorder that is characterized by social abnormalities. Genetic, dietary and gut-related factors are implicated in autism, however the causal properties of these factors and how they may interact are unclear. Propionic acid (PPA) is a product of gut microbiota and a food preservative. PPA has been linked to autism, and PPA administration to rats is an animal model of the condition. Seizure-prone (FAST) and seizure-resistant (SLOW) rats were initially developed to investigate differential vulnerability to developing epilepsy. However, FAST rats also display autistic-like features, and have been proposed as a genetic model of autism. Here we examined the effects of PPA on social behavior in FAST and SLOW rats. A single intracerebroventricular injection of PPA, or phosphate-buffered saline (PBS), was administered to young-adult male FAST and SLOW rats. Immediately after treatment, rats were placed in same-treatment and same-strain pairs, and underwent social behavior testing. PPA induced social abnormalities in both FAST and SLOW rat strains. While there was no evidence of social impairment in FAST rats that were not treated with PPA, these rats were hyperactive relative to SLOW rats. Post-mortem immunofluorescence analysis of brain tissue indicated that PPA treatment resulted in increased astrogliosis in the corpus callosum and cortex compared to PBS treatment. FAST rats had increased astrogliosis in the cortex compared to SLOW rats. Together these findings support the use of PPA as a rat model of autism, but indicate there are no interactive effects between the PPA and FAST models.
authors.affiliation: Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia. Electronic address: sshultz@unimelb.edu.au.
authors.forename: Sandy R
authors.initials: SR
authors.lastname: Shultz
authors.affiliation: Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Noor A B
authors.initials: NA
authors.lastname: Aziz
authors.affiliation: Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia; Department of Histology and Embryology, Kunming Medical University, Kunming, Yunnan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Mujun
authors.initials: M
authors.lastname: Sun
authors.affiliation: The Kilee Patchell-Evans Autism Research Group, Department of Psychology and Psychiatry, University of Western Ontario, London, ON, Canada.
authors.forename: Derrick F
authors.initials: DF
authors.lastname: MacFabe
authors.affiliation: Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007276:Injections, Intraventricular; D008124:Locomotion / Q000187:drug effects; D008297:Male; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology*; D012920:Social Behavior Disorders / Q000139:chemically induced*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D011422:Propionates; C029658:propionic acid
keywords: Animal model; Astrogliosis; Attention deficit hyperactivity disorder; Autism; Short chain fatty acid