TY - JOUR
T1 - Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia
AU - Spathopoulou, Angeliki
AU - Sauerwein, Gabriella A.
AU - Marteau, Valentin
AU - Podlesnic, Martina
AU - Lindlbauer, Theresa
AU - Kipura, Tobias
AU - Hotze, Madlen
AU - Gabassi, Elisa
AU - Kruszewski, Katharina
AU - Koskuvi, Marja
AU - Réthelyi, János M.
AU - Apáti, Ágota
AU - Conti, Luciano
AU - Ku, Manching
AU - Koal, Therese
AU - Müller, Udo
AU - Talmazan, Radu A.
AU - Ojansuu, Ilkka
AU - Vaurio, Olli
AU - Lähteenvuo, Markku
AU - Lehtonen, Šárka
AU - Mertens, Jerome
AU - Kwiatkowski, Marcel
AU - Günther, Katharina
AU - Tiihonen, Jari
AU - Koistinaho, Jari
AU - Trajanoski, Zlatko
AU - Edenhofer, Frank
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - 1182 Biochemistry, cell and molecular biology
KW - 3124 Neurology and psychiatry
U2 - 10.1038/s41380-024-02568-8
DO - 10.1038/s41380-024-02568-8
M3 - Article
AN - SCOPUS:85191800350
SN - 1359-4184
VL - 29
JO - Molecular Psychiatry
JF - Molecular Psychiatry
ER -