Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats

Shultz, Sandy R.; Aziz, Noor A.B.; Yang, Li; Sun, Mujun; MacFabe, Derrick F.; O’Brien, Terence J.

doi:10.1016/j.bbr.2014.10.050

Cited by 59 publications

(44 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Neuroinflammation (astrogliosis) was evident in these animals (Shultz et al, 2008). This same treatment also impaired cognition and sensorimotor ability in Long-Evans rats (Shultz et al, 2009;Shultz et al, 2015).…”

Section: Asd and Gut Microbiome Animal Model Studiesmentioning

confidence: 82%

Microbiome Disturbances and Autism Spectrum Disorders

2015

View full text Add to dashboard Cite

Autism spectrum disorders (ASDs) are considered a heterogenous set of neurobehavioral diseases, with the rates of diagnosis dramatically increasing in the past few decades. As genetics alone does not explain the underlying cause in many cases, attention has turned to environmental factors as potential etiological agents. Gastrointestinal disorders are a common comorbidity in ASD patients. It was thus hypothesized that a gut-brain link may account for some autistic cases. With the characterization of the human microbiome, this concept has been expanded to include the microbiota-gut-brain axis. There are mounting reports in animal models and human epidemiologic studies linking disruptive alterations in the gut microbiota or dysbiosis and ASD symptomology. In this review, we will explore the current evidence that gut dysbiosis in animal models and ASD patients correlates with disease risk and severity. The studies to date have surveyed how gut microbiome changes may affect these neurobehavioral disorders. However, we harbor other microbiomes in the body that might impact brain function. We will consider microbial colonies residing in the oral cavity, vagina, and the most recently discovered one in the placenta. Based on the premise that gut microbiota alterations may be causative agents in ASD, several therapeutic options have been tested, such as diet modulations, prebiotics, probiotics, synbiotics, postbiotics, antibiotics, fecal transplantation, and activated charcoal. The potential benefits of these therapies will be considered. Finally, the possible mechanisms by which changes in the gut bacterial communities may result in ASD and related neurobehavioral disorders will be examined.

show abstract

Section: Asd and Gut Microbiome Animal Model Studiesmentioning

confidence: 82%

Microbiome Disturbances and Autism Spectrum Disorders

2015

View full text Add to dashboard Cite

show abstract

“…A number of studies point that chronic intracerebroventricular, i.p., or intracutaneous treatment of rodents with different doses of PPA (4.0 μl, 250 and 500 mg/kg respectively) produces behavioural, immmunocytochemical and biochemical changes that are reminiscent with those in ASD (Choi et al, ; Foley, MacFabe, Vaz, Ossenkopp, & Kavaliers, ; MacFabe et al, ; Ossenkopp et al, ; Shultz et al, ). Unlike these studies, in the present investigation, the rats received a single i.p.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Lobzhanidze

Japaridze²,

Lordkipanidze

et al. 2020

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Short chain fatty acids, produced as gut microbiome metabolites but also present in the diet, exert broad effects in host physiology. Propionic acid (PPA), along with butyrate and acetate, plays a growing role in health, but also in neurological conditions. Increased PPA exposure in humans, animal models and cell lines elicit diverse behavioural and biochemical changes consistent with organic acidurias, mitochondrial disorders and autism spectrum disorders (ASD). ASD is considered a disorder of synaptic dysfunction and cell signalling, but also neuroinflammatory and neurometabolic components. We examined behaviour (Morris water and radial arm mazes) and the ultrastructure of the hippocampus and medial prefrontal cortex (electron microscopy) following a single intraperitoneal (i.p.) injection of PPA (175 mg/kg) in male adolescent rats. PPA treatment showed altered social and locomotor behaviour without changes in learning and memory. Both transient and enduring ultrastructural alterations in synapses, astro‐ and microglia were detected in the CA1 hippocampal area. Electron microscopic analysis showed the PPA treatment significantly decreased the total number of synaptic vesicles, presynaptic mitochondria and synapses with a symmetric active zone. Thus, brief systemic administration of this dietary and enteric short chain fatty acid produced behavioural and dynamic brain ultrastructural changes, providing further validation of the PPA model of ASD.

show abstract

“…After completion of the elevated-plus maze, locomotion and anxiety-like behavior was assessed using an open field as previously described (Shultz et al, 2015a). The rats were individually placed in a circular open arena (100 cm diameter, 20 cm high wall) and allowed to freely explore for 10 min.…”

Section: Behavioral Testingmentioning

confidence: 99%