EXPLORING THE EFFECTS OF DE NOVO MUTATIONS IN SCHIZOPHRENIA USING INDUCED PLURIPOTENT STEM CELLS
Tordai Csongor Balázs
Mentális Egészségtudományok
Dr. Bódizs Róbert
SE Pszichiátriai és Pszichoterápiás Klinika tanterme
2025-09-10 14:00:00
Pszichiátria
Dr. Réthelyi János
Dr. Réthelyi János, Dr. Apáti Ágota
Dr. Padányi Rita
Dr.Tárnok Krisztián
Dr. Kellermayer Miklós
Dr. Adorján István
Dr. Wittner Lucia
In my PhD thesis, I explored in vitro disease modeling of schizophrenia (SCZ) through two patient-focused projects. Both SCZ patients carried unique de novo mutations: one in the ZMYND11 gene and another in the KHSRP and LRRC7 genes. Using induced pluripotent stem cell (hiPSC) technology, we investigated how these mutations influence neuronal differentiation and function.
We successfully reprogrammed patient cells into hiPSCs and established control lines through two methods: creating isogenic lines via CRISPR editing for the ZMYND11 case and reprogramming parental cells for the KHSRP and LRRC7 case. These hiPSCs were differentiated into hippocampal neural progenitor cells (NPCs) and dentate gyrus granule cells (DGGCs) using a hippocampal differentiation protocol. Both SCZ and control lines formed functional NPCs and DGGCs, as evidenced by calcium transients and field potentials.
Transcriptomic analyses revealed significant differences in genes related to neuronal differentiation and synaptic function, indicating altered developmental pathways. Functional studies showed decreased glutamate reactivity in SCZ samples: in NPCs for KHSRP and LRRC7 mutations, and in DGGCs for ZMYND11 mutations.
Overall, our findings demonstrate that these mutations disrupt neuronal differentiation at the transcriptomic level and impair glutamatergic signaling at the functional level. These results support the neurodevelopmental theory of SCZ and highlight the role of glutamatergic neurotransmission and synaptic dysfunction in SCZ pathology. Our work identifies potential therapeutic targets and emphasizes the convergent molecular pathways underlying neuronal dysfunction in SCZ.
