Autism spectrum disorder (ASD) is a heterogeneous neurodevelopment disorder resulting from different etiological factors, both genetic and/or environmental. These factors can lead to abnormal neuronal development on dendrite and synaptic function at the central nervous system. Recent studies have shown that a subset of ASD patients display increased circulation levels of the tyrosine metabolite, p-cresol, related to chronic intestinal disorders because of dysbiosis of the intestinal microbiota. In particular, abnormal presence of intestinal Clostridium sp. has been linked to high levels of p-cresol in ASD children younger than 8 years. However, the role of p-cresol during development of the central nervous system is unknown. Here, we evaluated in vitro the effect of p-cresol on neurite outgrowth in N2a and PC12 cell lines and dendritic morphology, synaptic density, neuronal activity, and calcium responses in primary rat hippocampal neurons. p-cresol inhibits neural differentiation and neurites outgrowth in N2a and PC12 neuronal cell lines. In hippocampal neuronal cultures, Sholl's analysis shows a decrease in the dendritic arborization of neurons treated with p-cresol.Synaptic density analyzed with the synaptic markers Piccolo and Shank2 is diminished in hippocampal neurons treated with p-cresol. Electrically evoked intracellular calcium
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