Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model

Abstract

Autism spectrum disorder (ASD) is induced by complex hereditary and environmental factors. However, the mechanisms of ASD development are poorly understood. The purpose of this study was to identify standard indicators of this condition by comparing clinical, pathophysiological, and neurobehavioral features in an autism-like animal model. A total of 22 male Sprague-Dawley rats were randomly divided into control and 500 mg/kg propionic acid (PPA)-treated groups. Rats were subjected to behavioral tests, gene expression analyses, and histological analyses to detect pathophysiological and neurobehavioral alterations. Exploratory activity and non-aggressive behavior were significantly reduced in PPA-treated rats, whereas enhanced aggressive behavior during adjacent interactions was observed on day 14 after PPA administration. To evaluate gene expression after PPA administration, we analyzed hippocampal tissue using reverse transcription PCR. Glial fibrillary acidic protein was augmented in the PPA-treated group on day 14 after appearance of ASD-like behaviors by PPA administration, whereas octamer-binding transcription factor 4 expression was significantly decreased in the PPA-treated group. Histological evaluation revealed significantly reduced diameter and layer thickness of granule cells in PPA-treated rats compared with control rats. We conclude that PPA administration induced abnormal neural cell organization, which may have led to autism-like neurobehaviors, including increased aggressive behavior, reduced exploratory activity, and isolative and passive behaviors.

Systemic treatment with the enteric bacterial metabolic product propionic acid results in reduction of social behavior in juvenile rats: Contribution to a rodent model of autism spectrum disorder

“…Reduced activity levels and increased anxiety are also induced by immune system stimulation (Foster & Neufeld, ; Tenk, Kavaliers, & Ossenkopp, ) or cytokine treatment (Goehler, Lyte, & Gaykema, ). Several recent studies on the effects of systemic PPA treatment in the prenatal developmental stage, or early neonatal stage, have found that PPA treatment resulted in impaired social behavior and increased anxiety levels in adolescent animals (Choi et al, ; El‐Ansary, Al‐Daihan, & El‐Gezeery, ; Foley, MacFabe, Vaz, Ossenkopp, & Kavaliers, ; Foley, Ossenkopp, Kavaliers, & MacFabe, ), consistent with the present findings involving juvenile treatment with PPA. Systemic administration of PPA also has been shown to reduce startle reactivity in adult rats, in a dose‐dependent fashion (Kamen et al, ), another behavioral effect consistent with ASD symptomology.…”

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

“…Brains from PPA‐treated rodents show micro‐ and astroglial activation, mitochondrial and fatty acid dysfunction, increased the levels of neurotoxic cytokines and oxidative stress markers, and other alterations, consistent with the findings in human ASD (Choi et al, ; El‐Ansary et al, ; MacFabe et al, ; Mepham et al, ; Nankova et al, ; Shams et al, ). In addition to animal models, autism‐like biochemical alterations were found on PPA‐treated human lymphoblast cell lines (Frye et al, , ; Nankova et al, ; Rose et al, ) and human stem cells (Abdelli, Samsam, & Naser, ; Yang et al, , Neurochemistry, accepted for publication).…”

“…Many genes traditionally thought to be involved in autism encode cell adhesion molecules and proteins involved in neurogenesis, synaptogenesis, synaptic functions and other cellular processes (Chen, Chang, & Huang, ; Guang et al, ; Zhao et al, ). In addition to the genetic component, a number of environmental factors participate in autism pathogenesis, affecting synapse activities, neuroimmune regulation, gastrointestinal function, metabolism and gene expression (Choi et al, ; Huang & Jin, ; MacFabe, ; Rizzetto, Fava, Tuohy, & Selmi, ). Therefore, most of such conditions represent the consequence of interaction between individual's genetic profile and the environment that he/she is exposed to (Blatt, ).…”

“…Further to this we (Lobzhanidze et al, ; MacFabe, ; MacFabe et al, ; Shams, Foley, Kavaliers, MacFabe, & Ossenkopp, ; Shultz et al, , ), and others (Aabed et al, ; Choi et al, ; El‐Ansary et al, ) have used the exposure of PPA and related short chain fatty acid administration in rodents as an acceptable animal model of autism. It was shown that the rats, treated with PPA (intracerebroventricular, intraperitoneal, subcutaneous injections, intragastric gavage), exhibit many autism‐like behaviours, like repetitive, antisocial, anxiety‐like and repetitive behaviours, including dystonia and seizures.…”

“…Although PPA‐mediated autism‐like neurochemical and behavioural effects have been described in many studies, only a few reports of morphological consequences of PPA on the brain are available (Choi et al, ; Lobzhanidze et al, ; MacFabe et al, ; MacFabe, Cain, Boon, Ossenkopp, & Cain, ). Moreover, the description of the brain ultrastructure in the PPA and other animal models of autism are lacking.…”