Dataset Information

NSC-34 Motor Neuron-Like Cells Are Unsuitable as Experimental Model for Glutamate-Mediated Excitotoxicity.

ABSTRACT: Glutamate-induced excitotoxicity is a major contributor to motor neuron degeneration in the pathogenesis of amyotrophic lateral sclerosis (ALS). The spinal cord × Neuroblastoma hybrid cell line (NSC-34) is often used as a bona fide cellular model to investigate the physiopathological mechanisms of ALS. However, the physiological response of NSC-34 to glutamate remains insufficiently described. In this study, we evaluated the relevance of differentiated NSC-34 (NSC-34D) as an in vitro model for glutamate excitotoxicity studies. NSC-34D showed morphological and physiological properties of motor neuron-like cells and expressed glutamate receptor subunits GluA1-4, GluN1 and GluN2A/D. Despite these diverse characteristics, no specific effect of glutamate was observed on cultured NSC-34D survival and morphology, in contrast to what has been described in primary culture of motor neurons (MN). Moreover, a small non sustained increase in the concentration of intracellular calcium was observed in NSC-34D after exposure to glutamate compared to primary MN. Our findings, together with the inability to obtain cultures containing only differentiated cells, suggest that the motor neuron-like NSC-34 cell line is not a suitable in vitro model to study glutamate-induced excitotoxicity. We suggest that the use of primary cultures of MN is more suitable than NSC-34 cell line to explore the pathogenesis of glutamate-mediated excitotoxicity at the cellular level in ALS and other motor neuron diseases.

SUBMITTER: Madji Hounoum B

PROVIDER: S-EPMC4860417 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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NSC-34 Motor Neuron-Like Cells Are Unsuitable as Experimental Model for Glutamate-Mediated Excitotoxicity.

Madji Hounoum Blandine B Vourc'h Patrick P Felix Romain R Corcia Philippe P Patin Franck F Guéguinou Maxime M Potier-Cartereau Marie M Vandier Christophe C Raoul Cédric C Andres Christian R CR Mavel Sylvie S Blasco Hélène H

Frontiers in cellular neuroscience 20160509

Glutamate-induced excitotoxicity is a major contributor to motor neuron degeneration in the pathogenesis of amyotrophic lateral sclerosis (ALS). The spinal cord × Neuroblastoma hybrid cell line (NSC-34) is often used as a bona fide cellular model to investigate the physiopathological mechanisms of ALS. However, the physiological response of NSC-34 to glutamate remains insufficiently described. In this study, we evaluated the relevance of differentiated NSC-34 (NSC-34D) as an in vitro model for g ...[more]

PMID: 27242431

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Project description:Background Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in a triad of behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. OVT73 captures an early prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. Methods To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. Results We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in OVT73 medium spiny neurons, the cell type preferentially lost early in HD. This observation supports the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process. Moreover, we also observed the downstream consequences of excitotoxic stress, including a downregulation of transcription of components for the oxidative phosphorylation complexes. We also found that pathways whose activity has been proposed to reduce excitotoxicity, including the CREB family of transcription factors (CREB1, ATF2, ATF4 and ATF7) were transcriptionally downregulated. Conclusions To our knowledge, the OVT73 model is the first large mammal HD model that exhibits transcriptomic signatures of an excitotoxic process in the absence of neuronal loss. Our results suggest that glutamate excitotoxicity is a disease-initiating process. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.

Dataset Information

NSC-34 Motor Neuron-Like Cells Are Unsuitable as Experimental Model for Glutamate-Mediated Excitotoxicity.

Publications

NSC-34 Motor Neuron-Like Cells Are Unsuitable as Experimental Model for Glutamate-Mediated Excitotoxicity.

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