Figure 7.

Comparisons of the effects of TNF, SZ, and their combined effect on the organoid development. (A) Significant increase: +; significant decrease: −; significant differences: +/++,–/−−; non-significant trend (+), (−). The effects of TNF were either similar or less pronounced than of SZ. In some cellular changes, the effects of SZ+TNF were bigger than the individual factors. In one case, density of calretinin interneurons, the interaction between TNF and SZ reversed their individual effects (increases) to a marked loss of interneurons by SZ+TNF. (B) The relationship of INFS and altered neuronogenesis and oligodendrogenesis by TNF and in SZ. During brain development, the nuclear location of nFGFR1, which programs neuronal development, gradually increases as the proliferating neural progenitor cells (NPC) progress through neuroblasts to differentiating neurons that form cortical layers. The diverse SZ-linked mutations that disturb developmental signals and an increased TNF promote premature nuclear FGFR1 location leading to increased formation of neurons already within the VZ and IZ and reduced subcortical oligodendrocytic development. However, when cells reach the organoid surface, nFGFR1 is turned off, possibly by increased ECM signals (Stachowiak et al., 2017). The loss of nFGFR1 reduces formation of dense cortical neuronal networks, while increasing numbers of short calretinin interneurons, diminishing their preferred horizontal orientation, and promoting oligodendrocytes. The TNF-induced changes in C organoids are similar, although generally less pronounced than those occurring in SZ. On the other hand, the combined effect of SZ and TNF are often more pronounced or even opposite (loss of calretinin interneurons) from their individual effects, likely reflecting INFS dysregulation of TNF receptor signaling. Our findings suggest that the combined effects of the SZ genomic dysregulations and maternal immune activation (MIA) may increase the risk and/or severity of SZ.