Neuropathological and biochemical effects of dietary propionic acid in rats-further development of a rodent model of autism
Saturday, Nov 09, 2013, 2:00 PM - 3:00 PM
++C.07.k. Animal models and mechanisms
, L. TICHENOFF
, F. BOON
, R. THOMAS
, S. HOLBROOK
, D. F. MACFABE
Kilee Patchell-Evans Autism Res. Group-Dept. of Psychology,
Dept. of Psychology, Neurosci. Grad. Program,
Kilee Patchell-Evans Autism Res. Group- Depts of Psychology/Psychiatry, Western Univ., London, ON, Canada
Early antibiotic exposure, gastrointestinal symptoms, carbohydrate cravings, gut dysbiosis, mitochondrial dysfunction and altered lipid/oxidative stress markers are often associated in patients with autism spectrum disorders (ASD). Propionic acid (PPA) is a short-chain fatty acid (SCFA) that is a fermentation product of a subpopulation of ASD associated enteric bacteria (
clostridia, bacteroidetes, desulfovibrio
PPA along with other SCFAs (e.g., butyrate and acetate) can affect diverse physiological processes, such as cell signalling, mitochondrial/immune function and gene expression, among others. PPA and related SCFAs could provide a link among the disparate behavioural, dietary, gut, metabolic and immune factors implicated in ASD. Pulsed intracerebroventricular (ICV) infusions of PPA in adult rats produces many behavioural (repetitive/impaired social), electrophysiological (seizure, tics) neuropathological (innate neuroinflammatory) and biochemical (redox, altered phospholipid/acylcarnitine changes) consistent with a valid animal model of ASD. To extend this model through development, pregnant dams and their weaned offspring were fed a diet enriched with dietary PPA (dose 7%w/v, ad libitum), allowed to survive until post natal day 30 or 50, and then sacrificed. Brain, colon and liver tissue were examined neurohistologically (DAB immunohistochemistry/ hematoxylin & eosin), or biochemically (carnitine/acylcarnitines) for any ASD related changes.
Immunohistochemical analysis of brain from PPA treated pups (neocortex, hippocampal formation) revealed increased neuronal density (NeuN), synaptic density (synaptophysin), reactive astogliosis (GFAP), monocarboxylate I transporter and mitochondrial density/inclusions (COX IV), and decreased GABAergic neurons (parvalbumin). Histological analysis revealed evidence of liver steatosis and focal ileal colitis in PPA feed pups. Lipid analysis of forebrain homogenates from PPA treated pups revealed a relative carnitine deficiency/altered acylcarnitines. Further analysis is ongoing. Collectively these preliminary findings are consistent with pre and post natal dietary exposure of PPA inducing altered cortical migration, increased synaptic density, neuroinflammation, altered mitochondrial/carnitine metabolism, and reduced inhibitory interneurons, all consistent with findings in ASD patients. In summary, early pre and post natal dietary exposure of PPA may lead to enduring brain, hepatic and gut pathological and metabolic alterations in rats, further supporting SCFA administration in rodents as a valid animal model of ASD.
Autism Reserach Institute
GoodLife Children's Foundation
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