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Dysregulation of Intracellular Ca2+ in Dystrophic Cortical and Hippocampal Neurons

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Abstract

Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder characterized by skeletal muscle wasting, cardiomyopathy, as well as cognitive impairment. Lack of dystrophin in striated muscle produces dyshomeostasis of resting intracellular Ca2+ ([Ca2+]i), Na+ ([Na+]i), and oxidative stress. Here, we test the hypothesis that similar to striated muscle cells, an absence of dystrophin in neurons from mdx mice (a mouse model for DMD) is also associated with dysfunction of [Ca2+]i homeostasis and oxidative stress. [Ca2+]i and [Na+]i in pyramidal cortical and hippocampal neurons from 3 and 6 months mdx mice were elevated compared to WT in an age-dependent manner. Removal of extracellular Ca2+ reduced [Ca2+]i in both WT and mdx neurons, but the decrease was greater and age-dependent in the latter. GsMTx-4 (a blocker of stretch-activated cation channels) significantly decreased [Ca2+]i and [Na+]i in an age-dependent manner in all mdx neurons. Blockade of ryanodine receptors (RyR) or inositol triphosphate receptors (IP3R) reduced [Ca2+]i in mdx. Mdx neurons showed elevated and age-dependent reactive oxygen species (ROS) production and an increase in neuronal damage. In addition, mdx mice showed a spatial learning deficit compared to WT. GsMTx-4 intraperitoneal injection reduced neural [Ca2+]i and improved learning deficit in mdx mice. In summary, mdx neurons show an age-dependent dysregulation in [Ca2+]i and [Na+]i which is mediated by plasmalemmal cation influx and by intracellular Ca2+ release through the RyR and IP3R. Also, mdx neurons have elevated ROS production and more extensive cell damage. Finally, a reduction of [Ca2+]i improved cognitive function in mdx mice.

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Acknowledgements

Florida Heart Research Institute (JAA), IDAs University of California 3-V440LP2 (JRL) supported the research reported in this publication. We would like to thank Dr. Ray Zhang for his help in statistical analysis.

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Author notes

  1. Francisco Altamirano

    Present address: Department of Internal Medicine – Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA

Authors and Affiliations

  1. Department of Molecular Biosciences, University of California, Davis, CA, 95616, USA

    José R. Lopez & Francisco Altamirano

  2. Centro de Investigaciones Biomédicas, Mexico, México

    Juan Kolster

  3. Division of Neonatology, Mount Sinai Medical Center, Miami, FL, 33140, USA

    Arkady Uryash & José A. Adams

  4. HP2 INSERM 1042 Institut Jean Roget, Université Grenoble Alpes, BP170, 38042, Grenoble Cedex, France

    Eric Estève

Authors
  1. José R. Lopez
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  2. Juan Kolster
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  3. Arkady Uryash
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  4. Eric Estève
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  5. Francisco Altamirano
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  6. José A. Adams
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Corresponding author

Correspondence to José R. Lopez.

Electronic Supplementary Material

Supplementary Fig. 1

Expression of Dp71 and utrophin. a Representative Western blots of Dp71 and utrophin (UTR) and respective protein loading control Tubulin, in 3- and 6-month-old WT and mdx neurons. Expression of Dp71 and UTR was reduced in an age-dependent manner in cortical neurons of mdx mice. b Protein expression of Dp71 was significantly reduced in 3- and 6-month mdx neurons compared to age-matched WT (p < 0.001). c Protein expression of utrophin was also significantly reduced in both 3- and 6-month mdx neurons compared to age-matched WT (p < 0.001). (GIF 85 kb)

High resolution (TIFF 2355 kb)

Supplementary Fig. 2

Protein level of α- and β-dystroglycan and sarcoglycan. a. Representative Western blots of α (α-DG) and β (β-DG) dystroglycan and α (α-SG) and β (β-SG) sarcoglycan and respective protein loading control Tubulin in 3- and 6-month-old WT and mdx neurons. Expression of α- and β-dystroglycan was reduced in an age-dependent manner (p < 0.001) in mdx cortical neurons; however, the decrease was most marked for β- than α-dystroglycan. Expression of α- and β-sarcoglycan was also significantly different between WT and mdx at either 3 or 6 months. b Protein expression of α-DG was significantly reduced in 6-month mdx neurons compared to age-matched WT (p < 0.001). c Protein expression of β-DG was also significantly reduced in both 3- and 6-month mdx neurons compared to age-matched WT (p < 0.001). d α-SG was significantly reduced in mdx cortical neurons at both 3 and 6 months compared to WT (p < 0.01). e β-SG was also significantly reduced in mdx cortical neurons at both 3 and 6 months compared to WT (p < 0.001) (GIF 82 kb)

High Resolution (TIFF 2232 kb)

Supplementary Fig. 3

Transient receptor potential cation channel (TRPC)-1, TRPC-4, and TRPC-6 protein levels. a Representative Western blots of transient receptor potential cation channels (TRPC-1, TRPC-4, and TRPC-6) and respective protein loading control Tubulin, in 3- and 6-month-old WT and mdx neurons. b TRPC-1 expression was unchanged at 3 months between WT and mdx. In contrast, TRPC-1 was significantly overexpressed in 6-month-old mdx neurons compared to WT (p < 0.001). c TRPC-4 was significantly overexpressed in both 3- and 6-month mdx neurons compared to WT age-matched controls (p < 0.01). d TRPC-6 expression was unchanged at 3 months between WT and mdx but significantly overexpressed in 6-month-old mdx neurons compared to age-matched WT (p < 0.001). (GIF 102 kb)

High Resolution (TIFF 3184 kb)

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Lopez, J.R., Kolster, J., Uryash, A. et al. Dysregulation of Intracellular Ca2+ in Dystrophic Cortical and Hippocampal Neurons. Mol Neurobiol 55, 603–618 (2018). https://doi.org/10.1007/s12035-016-0311-7

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  • DOI: https://doi.org/10.1007/s12035-016-0311-7

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