Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic
and environmental factors. The etiology behind the disorder remains elusive although
it is hypothesized to be associated with the aberrant response to neurotransmitters,
such as dopamine and glutamate. Therefore, investigating the link between dysregulated
metabolites and distorted neurodevelopment holds promise to offer valuable insights
into the underlying mechanism of this complex disorder. In this study, we aimed to
explore a presumed correlation between the transcriptome and the metabolome in a SCZ
model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs
were differentiated towards cortical neurons and samples were collected longitudinally
at various developmental stages, reflecting neuroepithelial-like cells, radial glia,
young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted
metabolomics and the two modalities were used to construct integrative networks in
silico. This multi-omics analysis revealed significant perturbations in the polyamine
and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation
in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase
encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their
biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted
in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine
pathway as an alternative route for GABA production. These findings indicate an imbalance
of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental
stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits
to be causative for SCZ and establishes a novel in silico approach that enables for
integrative correlation of metabolic and transcriptomic data of psychiatric disease
models.
