Abstract:
Schizophrenia spectrum disorders (SCZ) are severe and complex mental diseases with a multifactorial disease aetiology, which are characterized by the interplay of genetic (e.g. copy number variants) and environmental factors. One major theory in psychiatry proposes aberrant dopamine neurotransmission associated with a hyperdopaminergic state in the striatum and a hypodopaminergic state in the prefrontal cortex contributing to positive and negative/cognitive symptoms, respectively. Detailed mechanistic insight into hypodopaminergic signalling in the mesocortical pathway, particularly the interactions between dopaminergic and glutamatergic neurons, is widely lacking. Another popular hypothesis postulates an imbalance in excitatory and inhibitory signalling in the prefrontal microcircuitry, which is accompanied by aberrant synaptic connectivity and neuronal network deficits. These characteristic features, observed in patients with neuropsychiatric disorders such as SCZ, are thought to result in cognitive symptoms.
To explore the interactions between dopaminergic and glutamatergic neurons in SCZ, a humanized iPSC-based in vitro co-culture model derived from patients with idiopathic SCZ was established. In addition, an isogenic co-culture model composed of iPSC-derived glutamatergic and GABAergic cortical neurons (E-I co-culture) carrying 15q13 and 22q11 microdeletions, as genetic risk factors for SCZ, was employed to better understand excitation-inhibition imbalance observed in SCZ and related neuropsychiatric disorders.
Transcriptome analysis of SCZ dopaminergic neurons revealed downregulation of early transcription factors, dopamine metabolism genes, as well as the autoreceptor DRD2 suggesting a hypodopaminergic phenotype and disinhibition of neuronal activity. Cell type-specific analysis revealed increased neuronal activity in both dopaminergic and glutamatergic SCZ neurons in co-culture, which was found to be mainly driven by SCZ dopaminergic neurons and was rescued by a selective DRD2 agonist. In addition, an excess loss of glutamatergic synapses was observed in SCZ co-cultures, whereas dopaminergic synapses remained unaffected. In E-I co-cultures carrying 15q13 and 22q11 microdeletions, a synaptic shift towards increased inhibition was observed, which was accompanied by decreased network activity, but increased synchronicity.
Overall, the established dopaminergic-glutamatergic co-culture model offers the possibility to study mutual interactions between dopaminergic and glutamatergic neurons in more detail and underpins the study of a hypodopaminergic phenotype in SCZ. Furthermore, findings of the microdeletion E I co-culture system support the hypothesis of an excitation-inhibition imbalance. Although both co-culture systems comprised distinct neuronal compositions, aberrant excitatory synapse formation was identified as an overarching feature.
iPSC