Affiliation:
1. Department of Biochemistry and Molecular Biology University of Oklahoma Health Sciences Center Oklahoma City Oklahoma USA
2. Center for Geroscience and Healthy Brain Aging Oklahoma City Oklahoma USA
3. Oklahoma City Veterans Health Care System Oklahoma City Oklahoma USA
4. Aging & Metabolism Research Program, Oklahoma Medical Research Foundation Oklahoma City Oklahoma USA
Abstract
AbstractThe mitochondrial calcium uniporter (MCU) is the main route of calcium (Ca2+) entry into neuronal mitochondria. This channel has been linked to mitochondrial Ca2+ overload and cell death under neurotoxic conditions, but its physiologic roles for normal brain function remain poorly understood. Despite high expression of MCU in excitatory hippocampal neurons, it is unknown whether this channel is required for learning and memory. Here, we genetically down‐regulated the Mcu gene in dentate granule cells (DGCs) of the hippocampus and found that this manipulation increases the overall respiratory activity of mitochondrial complexes I and II, augmenting the generation of reactive oxygen species in the context of impaired electron transport chain. The metabolic remodeling of MCU‐deficient neurons also involved changes in the expression of enzymes that participate in glycolysis and the regulation of the tricarboxylic acid cycle, as well as the cellular antioxidant defenses. We found that MCU deficiency in DGCs does not change circadian rhythms, spontaneous exploratory behavior, or cognitive function in middle‐aged mice (11–13 months old), when assessed with a food‐motivated working memory test with three choices. DGC‐targeted down‐regulation of MCU significantly impairs reversal learning assessed with an 8‐arm radial arm water maze but does not affect their ability to learn the task for the first time. Our results indicate that neuronal MCU plays an important physiologic role in memory formation and may be a potential therapeutic target to develop interventions aimed at improving cognitive function in aging, neurodegenerative diseases, and brain injury.image
Funder
American Federation for Aging Research
National Institute of General Medical Sciences
National Institute on Aging
Subject
Cellular and Molecular Neuroscience,Biochemistry
Cited by
3 articles.
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