Dysregulation of Intracellular Ca2+ in Dystrophic Cortical and Hippocampal Neurons

José R. Lopez, Juan Kolster, Arkady Uryash, Eric Estève, Francisco Altamirano, José A. Adams

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Dec 15 2016

Keywords

  • Calcium
  • Duchenne’s
  • GsMTx-4
  • Inositol triphosphate
  • Lactate dehydrogenase
  • Morris water maze
  • Neuron
  • Reactive oxygen species
  • Ryanodine
  • Sodium

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Lopez, J. R., Kolster, J., Uryash, A., Estève, E., Altamirano, F., & Adams, J. A. (Accepted/In press). Dysregulation of Intracellular Ca2+ in Dystrophic Cortical and Hippocampal Neurons. Molecular Neurobiology, 1-16. https://doi.org/10.1007/s12035-016-0311-7