Time Course of Propionic Acid Induced Lipid, Neuroinflammatory and Cognitive Deficits In the Morris Water Maze-Further Development of A Novel Rodent Model of Autism

Background: Autism spectrum disorders (ASD) are a cluster of neurodevelopmental disorders characterized by social deficits, cognitive abnormalities, and restricted interests.  ASD patients often show perseveration of behaviour, including difficulty adjusting to non-routine activities.  Dietary, infective and gastrointestinal factors have been suggested to co-exist with the development and fluctuation of ASD symptoms.  Propionic acid (PPA) is a dietary short chain fatty acid and a metabolic fermentation product of ASD-associated bacteria (i.e., Clostridia, Desulfovibrio).  Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioural, biochemical and neuropathological changes similar to findings in ASD patients, including bouts of hyperactivity, repetitive movements, perseveration, social impairment,  coupled with brain oxidative stress, altered lipid profiles, and innate neuroinflammation.  

Objectives: The time course and potential reversibility of the cognitive deficits associated with the PPA rodent model of ASD was assessed using adult male Long-Evans rats.   

Methods: ICV infusions of either PPA (0.26 M, pH 7.4, 4 µl/infusion) or phosphate buffered saline (PBS, 0.1 M) vehicle were given twice a day for 7 consecutive days.  Rats were then tested in the Morris water maze for acquisition on day 7 of infusions and then again one week later for reversal, and perseveratory behaviours were assessed.  In a second experiment, rats were subjected to the same infusion schedule, but were nonspatially pretrained in the maze prior to drug treatment.  Brain tissue was analyzed for lipid profiles and innate neuroinflammatory changes. 

Results: Compared to controls, both pretrained and non-pretrained PPA-treated rats showed longer search latencies to find the hidden platform, indicating impairment during spatial acquisition of the maze.  However, after a one-week recovery period these animals were able to reverse the maze at the same level as controls.  Examination of PPA treated brain tissue revealed qualitative altered lipid profiles and innate neuroinflammatory changes, which partially returned to baseline after this one-week recovery period. 

Conclusions: Prolonged exposure of PPA produced cognitive impairments, altered brain lipids and innate neuroinflammatory changes. However, some behavioural and brain changes from ICV infusions of PPA may be reversible upon discontinuation of exposure, providing further validity of this novel rodent model of ASD.