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DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons

1
Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
2
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
3
Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, 52074 Aachen, Germany
4
Research Training Group 2416 MultiSenses-MultiScales, Institute for Biology II, RWTH Aachen University, 52074 Aachen, Germany
5
Department of Chemosensation, Institute of Biology II, RWTH Aachen University, 52074 Aachen, Germany
*
Authors to whom correspondence should be addressed.
These authors contribute equally to this work.
Academic Editor: Claudio Grassi
Int. J. Mol. Sci. 2021, 22(4), 2034; https://doi.org/10.3390/ijms22042034
Received: 19 January 2021 / Revised: 8 February 2021 / Accepted: 13 February 2021 / Published: 18 February 2021
Epigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activity in excitatory and inhibitory cortical neurons in mice. Since DNA methylation signatures are responsive to neuronal activity, DNA methylation seems to contribute to the neuron’s capacity to adapt to and integrate changing activity patterns, being crucial for the plasticity and functionality of neuronal circuits. Since most studies addressing the role of DNA methylation in the regulation of synaptic function were conducted in mice or murine neurons, we here asked whether this functional implication applies to human neurons as well. To this end, we performed calcium imaging in human induced pluripotent stem cell (iPSC)-derived excitatory cortical neurons forming synaptic contacts and neuronal networks in vitro. Treatment with DNMT1 siRNA that diminishs the expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) was conducted to investigate the functional relevance of DNMT1 as one of the main enzymes executing DNA methylations in the context of neuronal activity modulation. We observed a lowered proportion of actively firing neurons upon DNMT1-knockdown in these iPSC-derived excitatory neurons, pointing to a correlation of DNMT1-activity and synaptic transmission. Thus, our experiments suggest that DNMT1 decreases synaptic activity of human glutamatergic neurons and underline the relevance of epigenetic regulation of synaptic function also in human excitatory neurons. View Full-Text
Keywords: DNMT1; human iPSC; layer 2/3 cortical neurons; synaptic activity; spontaneous activity; calcium imaging DNMT1; human iPSC; layer 2/3 cortical neurons; synaptic activity; spontaneous activity; calcium imaging
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MDPI and ACS Style

Bachmann, S.; Linde, J.; Bell, M.; Spehr, M.; Zempel, H.; Zimmer-Bensch, G. DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons. Int. J. Mol. Sci. 2021, 22, 2034. https://doi.org/10.3390/ijms22042034

AMA Style

Bachmann S, Linde J, Bell M, Spehr M, Zempel H, Zimmer-Bensch G. DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons. International Journal of Molecular Sciences. 2021; 22(4):2034. https://doi.org/10.3390/ijms22042034

Chicago/Turabian Style

Bachmann, Sarah, Jenice Linde, Michael Bell, Marc Spehr, Hans Zempel, and Geraldine Zimmer-Bensch. 2021. "DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons" International Journal of Molecular Sciences 22, no. 4: 2034. https://doi.org/10.3390/ijms22042034

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