Reference Work Entry

Comprehensive Guide to Autism

pp 1755-1778

Propionic Acid Animal Model of Autism

  • Sandy R. ShultzAffiliated withDepartment of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne Brain Centre Email author 
  • , Derrick F. MacFabeAffiliated withDepartments of Psychology and Psychiatry and Division of Developmental Disabilities, University of Western Ontario, The Kilee Patchell-Evans Autism Research Group


Autism spectrum disorders (ASD) are an increasing problem in Western society. Although largely genetic in nature, many environmental factors may play a role in triggering ASD in sensitive populations. Early antibiotic exposure, systemic immune and metabolic abnormalities, food cravings, and gastrointestinal comorbidities, which often relate to behavioral worsening, have been observed. Consequently, there is a growing need to develop animal models to examine how environmental factors relate to ASD pathogenesis. While growing evidence suggests that dietary or gut-related factors may influence brain function and symptomology in ASD patients, until recently no specific compounds have been identified which could provide a common explanation for the behavioral, biochemical, and neuropathological changes observed in ASD. This chapter will describe the recently developed propionic acid (PPA) rodent model of ASD and how its findings may relate to the clinical condition. PPA is a short-chain fatty acid that is endogenous to the human body as both an intermediary of fatty acid metabolism and a fermentation end product of antibiotic resistant enteric gut bacteria such as clostridia. Although largely derived in the gut, PPA and related short-chain fatty acids can readily gain access to the brain, where they can induce a diverse range of neurophysiological processes capable of altering both brain function and behavior. There are numerous lines of evidence suggesting that PPA and other enteric short-chain fatty acids may be elevated in ASD. To further examine the relationship between PPA and ASD, intracerebroventricular (ICV) injections of PPA in rats have recently been used as an animal model of ASD. Studies using this model have found that ICV treatment of PPA is capable of inducing numerous behavioral, electrophysiological, and neuropathological changes in rats that are consistent with those observed in ASD. Similar, but less pronounced, effects are also induced by ICV treatment of related gut short-chain fatty acids such as butyrate and sodium acetate. Together these findings suggest PPA and related short-chain fatty acids as putative risk factors for ASD and provide further evidence for a possible link between diet, metabolic, and/or gastrointestinal factors and ASD.