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Neuronal Differentiation of Induced Pluripotent Stem Cells from Schizophrenia Patients in Two-Dimensional and in Three-Dimensional Cultures Reveals Increased Expression of the Kv4.2 Subunit DPP6 That Contributes to Decreased Neuronal Activity.
- Source :
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Stem cells and development [Stem Cells Dev] 2020 Dec; Vol. 29 (24), pp. 1577-1587. Date of Electronic Publication: 2020 Nov 26. - Publication Year :
- 2020
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Abstract
- Although the molecular underpinnings of schizophrenia (SZ) are still incompletely understood, deficits in synaptic activity and neuronal connectivity have been identified as core pathomechanisms of SZ and other neuropsychiatric disorders. In this study, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts from healthy donors and patients diagnosed with idiopathic SZ. We differentiated the human iPSC into cortical neurons both as adherent monolayers and as three-dimensional spheroids. RNA sequencing revealed little overlap in differentially expressed genes between 2D and 3D neuron cultures from SZ iPSC compared with controls. Notably, mRNA transcripts encoding dipeptidyl peptidase-like protein 6 (DPP6), an accessory subunit of Kv4.2 voltage-gated potassium channels, were massively increased in cortical neurons from SZ iPSC in the 2D and 3D model. Consistently, multielectrode array recordings and calcium imaging showed significantly decreased neuronal activity both in 2D and in 3D cultures from SZ neurons. To show a causal relationship, we treated iPSC-derived neurons in 2D cultures with lentiviral DPP6 shRNA vectors and the Kv4.2 channel blocker AmmTx3, respectively. Both treatments successfully reversed neuronal hypoexcitability and hypoactivity in cortical neurons from SZ iPSC. Our data highlight a contribution of DPP6 and Kv4.2 to the deficit in neurotransmission in an iPSC model for SZ, which may be of therapeutic relevance for a subset of SZ patients.
- Subjects :
- Calcium metabolism
Cell Proliferation
Cell Survival
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases metabolism
GABAergic Neurons metabolism
Gene Expression Regulation
Glutamic Acid metabolism
Humans
Nerve Tissue Proteins metabolism
Neural Stem Cells metabolism
Potassium Channels metabolism
Protein Subunits metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Shal Potassium Channels metabolism
Spheroids, Cellular pathology
Synapses metabolism
Tissue Donors
Cell Culture Techniques
Cell Differentiation
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases genetics
Induced Pluripotent Stem Cells pathology
Nerve Tissue Proteins genetics
Neurons pathology
Potassium Channels genetics
Protein Subunits genetics
Schizophrenia pathology
Shal Potassium Channels genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-8534
- Volume :
- 29
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Stem cells and development
- Publication Type :
- Academic Journal
- Accession number :
- 33143549
- Full Text :
- https://doi.org/10.1089/scd.2020.0082