A co-culture model of dopaminergic and glutamatergic neurons derived from patients with idiopathic schizophrenia reveals a hypodopaminergic phenotype

Schizophrenia (SCZ) is a severe neurodevelopmental mental disorder characterised by a complex and multifactorial disease aetiology. Patients can suffer from both positive symptoms (e.g. hallucinations) and negative symptoms (e.g. social withdrawal) as well as cognitive impairments. The former are currently discussed to be caused by a hyperdopaminergic state in the striatum, whereas for the latter a hypodopaminergic state in the prefrontal cortex (PFC) is hypothesised. However, the underlying mechanism of hypodopaminergic signalling in the PFC, especially via the mesocortical pathway, is currently not known to any great detail. By analysing the transcriptome of iPSC-derived dopaminergic neurons from SCZ patients, we found that genes involved in dopaminergic differentiation as well as in dopamine synthesis and transport were downregulated. Furthermore, the expression of the D2 subtype of the dopamine receptor (DRD2) was also decreased, suggesting a hypodopaminergic phenotype and disinhibition of neuronal activity. Calcium imaging of a purely SCZ co-culture of human dopaminergic and glutamatergic telencephalic neurons revealed increased activity of both types of neurons, which was selectively reduced by a DRD2 agonist. Further quantification of synapse marker densities indicated a loss of glutamatergic synapses both on NGN2 and ALN neurons, whereas dopaminergic synapses were unaffected. Using mixed co-cultures comprising glutamatergic/dopaminergic neurons from healthy controls and SCZ patients, calcium imaging identified SCZ-ALN neurons as a major driver of increased activity in SCZ. Thus, the proposed model may be useful for the study of hypodopaminergic phenotypes of schizophrenia.