Mitochondrial calcium uniporter deficiency in dentate granule cells remodels neuronal metabolism and impairs reversal learning

Abstract

The 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

The mitochondrial calcium uniporter inhibitor Ru265 increases neuronal excitability and reduces neurotransmission via off‐target effects

“…For example, reducing MCU expression in haplo-insufficient mice increased the impact of high frequency firing on cytosolic Ca 2+ load and increased the magnitude of long-term potentiation (Devine et al, 2022). Brainspecific MCU loss reduced synchrony of hippocampal network oscillations and impaired learning behaviours (Bas-Orth et al, 2019;Rose et al, 2023). Thus, we speculate that specific, acute MCU inhibition may impair high-level cognitive performance, a potential concern for…”

Simultaneous quantitative respirometry and fluorometric assays in dissected hippocampal tissue from mice

“…We have successfully used the assessment of O 2 consumption in hippocampal tissue to study how cellular metabolism impacts cognitive decline. 1 , 2 …”

“… 2 in samples obtained from bulk hippocampal tissue, published in PNAS Nexus , and the study of Rose et al. 1 in dissected hippocampal slices, published in the Journal of Neurochemistry . Elements in the graphical abstract, along with Figures 1 and 2 , were created with BioRender.com .…”