While there is solid evidence that the neuropathologies of SZ often precede symptom onset, there are also clear adolescent neurobiological developmental processes (GABAergic maturation, excitatory synaptic pruning, microglia- and astrocyte-mediated neuroinflammation) and environmental exposures (cannabis abuse, stress) that can accelerate or exacerbate genetic risk (well-reviewed van Os et al., 2010). Moving forward, there is an urgent need to add further complexity to our hiPSC-based models in order to model these additional processes. Such efforts will involve not just improving the complexity of cell types, regional patterning and circuit formation, but also the restoration of critical features of “age” and “maturity” to hiPSC-derived cultures. While reprogramming of fibroblasts into hiPSCs erases age-related epigenetic marks and gene expression profiles, these can be at least partially maintained by inducing patient somatic cells directly into neurons (Mertens et al., 2015; Huh et al., 2016). Moreover, some environmental insults may be relatively easy to introduce, such as maternal infection/stress during development (Boksa, 2008), cannabis use (Henquet et al., 2005) or hypoxia during delivery (Cannon et al., 2002), while others such as trauma from childhood abuse and neglect (Read et al., 2005) may only be vaguely approximated by stress-related molecules such as corticosteroids or inflammatory cytokines.
