Chronic Electrical Stimulation Promotes the Excitability and Plasticity of ESC-derived Neurons following Glutamate-induced Inhibition In vitro

Latchoumane, C.-F. V.; Jackson, L.; Eslampanah Sendi, M. S.; Tehrani, K. F.; Mortensen, L. J.; Stice, S. L.; Ghovanloo, M.; Karumbaiah, L.

doi:10.1101/354191

bioRxiv · 10.1101/354191

Chronic Electrical Stimulation Promotes the Excitability and Plasticity of ESC-derived Neurons following Glutamate-induced Inhibition In vitro

Latchoumane, C.-F. V.·Jackson, L.·Eslampanah Sendi, M. S.·Tehrani, K. F.·Mortensen, L. J.·Stice, S. L.·Ghovanloo, M.·Karumbaiah, L.

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Abstract

Functional electrical stimulation (FES) is rapidly gaining traction as a therapeutic tool for mediating the repair and recovery of the injured central nervous system (CNS). However, the underlying mechanisms and impact of these stimulation paradigms at a molecular, cellular and network level remain largely unknown. In this study, we used embryonic stem cell (ESC)-derived neuron and glial cocultures to investigate network maturation following acute administration of L-glutamate, which is a known mediator of excitotoxicity following CNS injury. We then modulated network maturation using chronic low frequency stimulation (LFS) and direct current stimulation (DCS) protocols. We demonstrated that L-glutamate impaired the rate of maturation of ESC-derived neurons and glia immediately and over a week following acute treatment. The administration of chronic LFS and DCS protocols individually following L-glutamate infusion significantly promoted the excitability of neurons as well as network synchrony, while the combination of LFS/DCS did not. qRT-PCR analysis revealed that LFS and DCS alone significantly up-regulated the expression of excitability and plasticity-related transcripts encoding N-methyl-D-aspartate (NMDA) receptor subunit (NR2A), brain-derived neurotrophic factor (BDNF) and Ras-related protein (RAB3A). In contrast, the simultaneous administration of LFS/DCS down-regulated BDNF and RAB3A expression. Our results demonstrate that LFS and DCS stimulation can modulate network maturation excitability and synchrony following the acute administration of an inhibitory dose of L-glutamate, as well as an upregulation of NR2A, BDNF and RAB3A gene expression. Our study also provides a novel framework for investigating the effects of electrical stimulation on neuronal responses and network formation/repair after traumatic brain injury.

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Latchoumane, C.-F. V., Jackson, L., Eslampanah Sendi, M. S., Tehrani, K. F., Mortensen, L. J., Stice, S. L., Ghovanloo, M., Karumbaiah, L.. 2018-06-22. Chronic Electrical Stimulation Promotes the Excitability and Plasticity of ESC-derived Neurons following Glutamate-induced Inhibition In vitro. https://doi.org/10.1101/354191

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