Dietary and gastrointestinal factors may be associated with behavioural fluctuations in autism spectrum disorders (ASD). Furthermore, unique enteric bacterial species as well as immune and metabolic alterations have been observed, but their relation to these behavioural changes are unknown. Propionic acid (PPA) is a dietary short chain fatty acid that is an intermediary of fatty acid metabolism, a fermentation by-product of ASD-associated opportunistic enteric bacteria (ie clostridia), and a common food preservative. PPA has broad effects on neurotransmitter synthesis and release, calcium signaling, cell-cell interaction, mitochondrial metabolism, immune function and gene expression. PPA administration in rats has been shown to mimic many features of ASD.
Objectives:
We have found that repeated intracerebroventricular infusions of PPA produces bouts of hyperactivity, repetitive movements, retropulsion, object fixation and social impairments. Brain tissue from PPA treated rats shows ASD-like changes in oxidative stress markers, lipid profiles and innate neuroinflammation. However the exact mechanisms of PPA exposure and its temporal relation to behaviour remain unknown.
Methods:
Using a single pulse injection paradigm, we studied the relationship between PPA induced locomotor activity, lipid and neuropathological changes across specific time points. Adult Long-Evans rats were intraventricularly infused with 4ul of a 0.26M solution of PPA (pH 7.5) or a 0.1M solution of PBS vehicle. Locomotor activity (Ethovision) was evaluated for 20 minutes immediately following infusion and again 48 hours later to assess reversibility. Rats were sacrificed at various timepoints (30 minutes , 1 hour , 24 hours or 48 hours) post-injection, and brain tissue extracted to biochemically (lipids) and immunohistochemically analyze the latencies of PPA induced alterations.
Results:
PPA rapidly increased locomotor activity and achieved a maximal response within 20 minutes of infusion and returned to baseline measures within 48 hours. Alterations in brain phospholipid/acylcarnitine profiles transiently changed in relation to behaviour and preceded innate neuroinflammatory changes, the latter of which occurred when locomotor activity had returned to baseline.
Conclusions:
PPA rapidly increased locomotor activity and achieved a maximal response within 20 minutes of infusion and returned to baseline measures within 48 hours. Alterations in brain phospholipid/acylcarnitine profiles transiently changed in relation to behaviour and preceded innate neuroinflammatory changes, the latter of which occurred when locomotor activity had returned to baseline.