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

Abstract

The role of the gut microbiome and its enteric metabolites, such as short‐chain fatty acids (SCFAs), in the etiology of autism spectrum disorders (ASDs) has recently received increased attention. Of particular interest has been the SCFA, propionic acid (PPA). Several different rodent models have been developed using PPA treatment to examine behaviors of relevance to ASD. The effects of systemic (intraperitoneal, i.p.) administration of PPA on social behavior, anxiety‐related behavior, and locomotor activity in juvenile male rats (age 35 days) were examined in this study. Rats received seven i.p. injections of buffered PPA (500 mg/kg) or phosphate‐buffered saline. Behavior was video‐recorded during social interaction in a large open field (first four injections) or assessed in an automated activity system (individual animals, last three injections). PPA treatment significantly reduced social interaction, increased anxiety‐related behavior, and produced hypoactivity and increased abnormal motor movements. These findings suggest that PPA alters behaviors of relevance to ASD in juvenile rats. These results contribute to the behavioral validity of the rodent model of ASD with systemic PPA treatment.

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

“…Social impairment is one of the key characteristics of ASD and PPA treatments (Foley et al, 2014;MacFabe et al, 2007; F I G U R E 6 The assessment of locomotor activity in OF. PPA treated rats show significant decrease of locomotor activity when testing in OF Shams et al, 2019;Shultz et al, 2008). Previously, using the same regime of PPA injection as in the present study, we reported measurable social deficits 120 min after the PPA treatment (Lobzhanidze et al, 2019).…”

“…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).…”

“…Social impairment is one of the key characteristics of ASD and PPA treatments (Foley et al, ; MacFabe et al, ; Shams et al, ; Shultz et al, ). Previously, using the same regime of PPA injection as in the present study, we reported measurable social deficits 120 min after the PPA treatment (Lobzhanidze et al, ).…”

“…Several data point to such duality of the PPA effect. Thus, hypoactivity, hypotonia and abnormal motor movements are often detected in rodents chronically treated with PPA (Ossenkopp et al, ; Shams et al, ). In contrast, female offspring of rats prenatally exposed to PPA were significantly more active than vehicle‐treated females (Foley et al, ).…”

“…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.…”