1. In Vitro Differentiated Human Stem Cell-Derived Neurons Reproduce Synaptic Synchronicity Arising during Neurodevelopment
- Author
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G. Dulini C. Mendis, Gina E. Elsen, Snezana Maljevic, Melissa Castillo-Lizardo, Filip Rosa, Betuel Uysal, Felicitas Becker, Stephan Mueller, Ashutosh Dhingra, Claire E Cuddy, Christopher A. Reid, Peter Heutink, Steven Petrou, Holger Lerche, Heidi Loeffler, and Niklas Schwarz
- Subjects
0301 basic medicine ,Nervous system ,Cellular differentiation ,Embryoid body ,growth & development [Nervous System] ,Nervous System ,Biochemistry ,NGN2 ,0302 clinical medicine ,disease modeling ,Induced pluripotent stem cell ,Neurons ,ion channels ,Cell Differentiation ,dual SMAD ,medicine.anatomical_structure ,metabolism [Neurons] ,oscillations ,Stem cell ,cytology [Embryoid Bodies] ,neuronal network activity ,iPSCs ,Nerve Tissue Proteins ,Biology ,Models, Biological ,Article ,03 medical and health sciences ,Glutamatergic ,Genetics ,medicine ,Humans ,ddc:610 ,human neurons ,development ,Embryoid Bodies ,Cell Proliferation ,metabolism [Nerve Tissue Proteins] ,Sodium channel ,metabolism [Synapses] ,Cell Biology ,electrophysiology ,Electrophysiological Phenomena ,Electrophysiology ,030104 developmental biology ,nervous system ,Synapses ,cytology [Neurons] ,Neuroscience ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Summary Neurons differentiated from induced pluripotent stem cells (iPSCs) typically show regular spiking and synaptic activity but lack more complex network activity critical for brain development, such as periodic depolarizations including simultaneous involvement of glutamatergic and GABAergic neurotransmission. We generated human iPSC-derived neurons exhibiting spontaneous oscillatory activity after cultivation of up to 6 months, which resembles early oscillations observed in rodent neurons. This behavior was found in neurons generated using a more “native” embryoid body protocol, in contrast to a “fast” protocol based on NGN2 overexpression. A comparison with published data indicates that EB-derived neurons reach the maturity of neurons of the third trimester and NGN2-derived neurons of the second trimester of human gestation. Co-culturing NGN2-derived neurons with astrocytes only led to a partial compensation and did not reliably induce complex network activity. Our data will help selection of the appropriate iPSC differentiation assay to address specific questions related to neurodevelopmental disorders., Graphical Abstract, Highlights • Spontaneous oscillatory activity in iPSC-derived neurons after 4–6 months in culture • The activity resembled early oscillations seen in rodent neurons during development • Cell growth affects developmental changes of neuronal excitability • Biological age of neurons is determined based on electrophysiological activity, Rosa and colleagues have used two neural differentiation protocols to obtain induced pluripotent stem cell-derived neuronal cultures and address their relevance for the modeling of neurogenetic disorders. In neurons generated using one of the approaches, they report spontaneously occurring oscillations with properties corresponding to the neuronal activity seen during rodent and human brain development.
- Published
- 2020
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