Abstract
Propionic acid (PPA) is a short-chain fatty acid that is an important mediator of cellular metabolism. It is also a by-product of human gut enterobacteria and a common food preservative. A recent study found that rats administered with PPA showed autistic-like behaviors like restricted interest, impaired social behavior, and impaired reversal in a T-maze task. This study aimed to identify a link between PPA and autism phenotypes facilitated by signaling mechanisms in hippocampal neurons. Findings indicated autism-like pathogenesis associated with reduced dendritic spines in PPA-treated hippocampal neurons. To uncover the mechanisms underlying this loss, we evaluated autophagic flux, a functional readout of autophagy, using relevant biomedical markers. Results indicated that autophagic flux is impaired in PPA-treated hippocampal neurons. At a molecular level, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway was activated and autophagic activity was impaired. We also observed that a MAPK inhibitor rescued dendritic spine loss in PPA-treated hippocampal neurons. Taken together, these results suggest a previously unknown link between PPA and autophagy in spine formation regulation in hippocampal neurons via MAPK/ERK signaling. Our results indicate that MAPK/ERK signaling participates in autism pathogenesis by autophagy disruption affecting dendritic spine density. This study may help to elucidate other mechanisms underlying autism and provide a potential strategy for treating ASD-associated pathology.
Highlights
IntroductionReports on its influences on the immune system [1], metabolic processes [2], gene expression [3, 4], and nervous system [5] have led to increased recognition of the importance of the gut microbiome in human health and disease
The human microbiome represents a diverse ecosystem of microbes
propionic acid (PPA) induces the dendritic spine defects in hippocampal neurons We evaluated the effect of PPA on hippocampal neurons using pH and cell viability assays
Summary
Reports on its influences on the immune system [1], metabolic processes [2], gene expression [3, 4], and nervous system [5] have led to increased recognition of the importance of the gut microbiome in human health and disease. The relationship between the gut microbiome and nervous system as a significant component of the gut-brain axis has attracted increasing interest in recent. High levels of PPA, but not other SCFAs, have been reported in the stools of autistic spectrum disorder (ASD) individuals [15]. Studies have demonstrated that intraventricular infusions of PPA caused abnormal behavioral patterns, such as abnormal social interaction and anxiety-like behavior in rats similar to those seen in humans with ASD [14, 16]. There is growing evidence that PPA can affect behavioral development, the direct effects of PPA on neuronal cells remain poorly understood
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