Abstract

The lack of available relevant human tissue hampers efficient preclinical research and drug development for neurobiological diseases. By using induced pluripotent stem cells (iPSCs), this shortage can be bypassed, allowing to model human pathologies in an isogenic background.

Thus, disease-specific key cell types not accessible by biopsies can be analysed in vitro, and the interplay of these cell types can be studied in reconstituted co-culture systems.

In schizophrenia, a dysbalanced excitatory-inhibitory microcircuitry in the prefrontal cortex is suggested to contribute to the development of cognitive symptoms. Supporting this hypothesis, a grey matter volume reduction, as well as altered patterns of neuronal activity, have been described in patients.

By using CRISPR-mediated gene editing, we have caused deletions of a gene implicated in schizophrenia (DISC1, disrupted in schizophrenia 1). We employed induced pluripotent stem cells (iPSCs), which allowed us to differentiate them into neurons, and studied neurobiological parameters.

Several key aspects of patient pathophysiology were reflected in the iPSC-derived neuronal cells in vitro:

•       We show that DISC1 mutant neurons exhibit differentiation deficits and neurite outgrowth deficits.

•       In a co-culture model of excitatory and inhibitory iPSC-derived neurons, calcium activity patterns are affected in inhibitory interneurons

•       The density of inhibitory synapses on glutamatergic neurons is increased.

Our findings support the notion of interneuron dysfunctions in the cortex, which are believed to result in a reduction of high-frequency brain oscillations as previously identified in patients suffering from schizophrenia.