title: Dysregulation of Intracellular Ca2+in Dystrophic Cortical and Hippocampal Neurons.
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+]ihomeostasis and oxidative stress. [Ca2+]iand [Na+]iin 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+]iin 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+]iand [Na+]iin an age-dependent manner in all mdx neurons. Blockade of ryanodine receptors (RyR) or inositol triphosphate receptors (IP3R) reduced [Ca2+]iin 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+]iand improved learning deficit in mdx mice. In summary, mdx neurons show an age-dependent dysregulation in [Ca2+]iand [Na+]iwhich 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+]iimproved cognitive function in mdx mice.
authors.affiliation: Department of Molecular Biosciences, University of California, Davis, CA, 95616, USA. jrlopez@ucdavis.edu.
authors.forename: José R
authors.initials: JR
authors.lastname: Lopez
authors.affiliation: Centro de Investigaciones Biomédicas, Mexico, México.
authors.forename: Juan
authors.initials: J
authors.lastname: Kolster
authors.affiliation: Division of Neonatology, Mount Sinai Medical Center, Miami, FL, 33140, USA.
authors.forename: Arkady
authors.initials: A
authors.lastname: Uryash
authors.affiliation: HP2 INSERM 1042 Institut Jean Roget, Université Grenoble Alpes, BP170, 38042, Grenoble Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Estève
authors.affiliation: Department of Molecular Biosciences, University of California, Davis, CA, 95616, USA.|Department of Internal Medicine - Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Altamirano
authors.affiliation: Division of Neonatology, Mount Sinai Medical Center, Miami, FL, 33140, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Adams
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000473:pathology*; D003071:Cognition; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D012964:Sodium; D007770:L-Lactate Dehydrogenase; D002118:Calcium
keywords: Calcium; Duchenne’s; GsMTx-4; Inositol triphosphate; Lactate dehydrogenase; Morris water maze; Neuron; Reactive oxygen species; Ryanodine; Sodium