PhD Scientific Days 2021

MH_I_P: Mental Health Sciences I. Posters

In vitro modeling of schizophrenia by induced pluripotent stem cell-based technique: role of de novo mutations in functional assays

Text of the abstract

Introduction: Schizophrenia (SZ) is a highly heritable chronic psychiatric disorder characterized by hallucinations, delusions, cognitive dysfunction, and decreased community functioning. How genetic risk variants translate to disease-causing biologic alterations remains in most of the cases unknown. Among different kinds of genetic variations, de novo mutations (DNMs) have also been implicated in the etiology. Several DNMs have been identified by examining SZ cases and their unaffected parents.
Aims: We have developed an approach of using induced pluripotent stem cell (iPSC) lines from each member of a SZ case-parent trio, in order to investigate the effects of DNMs in cellular progenies of interest, particularly in dentate gyrus neuronal progenitors.
Method: We identified a male SZ patient characterized by early disease onset and negative symptoms, who is a carrier of 3 non-synonymous DNMs in genes LRRC7, KHSRP, and KIR2DL1. iPSC lines were generated from his and his parents’ peripheral blood mononuclear cells using Sendai virus-based reprogramming and differentiated into neuronal progenitor cells (NPCs) and hippocampal dentate gyrus granule cells. We used RNASeq to explore transcriptomic differences and calcium (Ca2+) imaging, cell proliferation, migration, oxidative stress, and mitochondrial assays to characterize the investigated NPC lines.
Results: NPCs derived from the SZ patient exhibited transcriptomic differences related to Wnt signaling, neuronal differentiation, axonal guidance, synaptic function, and decreased Ca2+ reactivity to glutamate. Moreover, we could observe increased cellular proliferation and alterations in mitochondrial quantity and morphology.
Conclusions: The approach of reprogramming case-parent trios represents an opportunity for investigating the molecular effects of disease-causing mutations and comparing these in cell lines with reduced variation in genetic background. Our study investigated only one family; therefore, the generalizability of findings is limited. The transcriptomic and functional assays were limited to the NPC stage, although these variables should also be investigated at the mature neuronal stage.
Funding: NAP 2017-1.2.1-NKP-2017-00002 grant, Semmelweis 250+ Kiválósági PhD Ösztöndíj (EFOP-3.6.3-VEKOP-16-2017-00009)

University and Doctoral School

Semmelweis University, Doctoral School of Mental Health Sciences