Sommer, I. E. C. | bioRxiv Science

bioRxiv2025

A human multilineage gut organoid model for Parkinson disease

Emerging evidence links gut dysfunction to Parkinson disease (PD) pathogenesis, yet human models to study gut-related mechanisms are lacking. We developed a human intestinal organoid model incorporating PD-relevant cell types. Using control and PD patient-derived pluripotent stem cells, we generated intestinal epithelial organoids and vagal neural crest cells, then co-cultured them into assembloids. The resultant structures featured lumen-forming polarized epithelial monolayers with enteroendocrine cells, contractile subepithelial myofibroblast-like layers, and neuroglial networks containing dopaminergic and cholinergic enteric neurons. Notably, assembloids from a PD patient carrying the GBA1-E326K variant exhibited progressive -synuclein accumulation in non-enteroendocrine epithelial cells. This model recapitulates key gut architecture and PD-associated phenotypes, offering a physiologically relevant platform for mechanistic studies and therapeutic discovery targeting gut-brain pathways in PD.

cell biology↗

bioRxiv2025

Apomorphine susceptibility and prenatal infection alter neurodevelopment, synaptic density and anticipatory behavior in rats

Schizophrenia is a complex psychiatric disorder, driven by genetic and environmental factors. While individual risk genes have limited impact, polygenic susceptibility increases the likelihood of schizophrenia and heightens sensitivity to environmental stressors, such as prenatal immune activation. Yet, preclinical studies often focused on single-gene mutations, leaving polygenic influences largely unexplored. Using the apomorphine-susceptible (APO-SUS) rat model, which exhibits schizophrenia-like features, we investigated how polygenic susceptibility influences early neurodevelopment, synaptic density, and behavior, and how these effects are modulated by prenatal immune activation. APO-SUS rats demonstrated early neurodevelopmental abnormalities, including a reduced number and duration of separation-induced ultrasonic vocalizations (USVs), increased principal frequency of USVs, and reduced heart rate variability (HRV), indicative of heightened sympathetic dominance commonly seen in psychiatric disorders. These effects were particularly pronounced in females. Male APO-SUS rats exhibited elevated synaptophysin levels, a presynaptic marker for synaptic density, in the frontal cortex during adolescence and in the hippocampus during adulthood. Interestingly, prenatal immune activation counteracted some of these changes, preventing HRV reduction and normalizing synaptophysin levels. Male and female APO-SUS rats, as well as Wistar male rats exposed to prenatal immune activation, showed anticipatory behavior during adolescence, but not in adulthood. Our results suggest that polygenic susceptibility induces early neurodevelopmental changes and that genetic and environmental risk factors do not always act synergistically; sometimes counterbalancing each other. Future studies should explore how early neurodevelopmental changes, such as alterations in USVs and HRV, influence later behavioral outcomes in polygenic models of schizophrenia. HighlightsO_LIApomorphine-susceptible rats show altered vocalizations and heart rate variability C_LIO_LIApomorphine susceptibility increases synaptophysin in frontal cortex and hippocampus C_LIO_LIPrenatal immune activation reduces synaptophysin in the adult frontal cortex C_LIO_LIPrenatal immune activation prevents apomorphine-susceptible brain and behavior changes C_LI

animal behavior and cognition↗