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Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
Reduced adolescent-age spatial learning ability associated with elevated juvenile-age superoxide levels in complex I
Johannes Mayer1, Gesine Reichart1, Tursonjan Tokay2
1Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, Germany.
Abstract:
Large-scale, heteroplasmic and generally pathogenic mtDNA defects (as induced by defective mitochondrial DNA polymerase, clonal mutations or DNA deletions) are known to negatively impact on life span and can result in apoptosis and tissue loss in, e.g., skeletal muscle or reduce learning abilities. The functional impact of homoplasmic specific mtDNA point mutations, e.g., in genes coding for the electron transport chain, however, remains a matter of debate. The present study contributes to this discussion and provides evidence that a single point mutation in complex I of the respiratory chain is associated with impairment of spatial navigation in adolescent (6-month-old) mice, i.e., reduced performance in the Morris Water Maze, which goes along with increased production of reactive oxygen species (ROS) in juvenile mice (3 months) but not at the age of phenotype expression. A point mutation in complex III goes along with only a mild and non-significant negative effect on cognitive performance and no significant changes in ROS production. These findings suggest to also consider the ontogenetic development of phenotypes when studying mtDNA mutations and highlights a possible impact of complex I dysfunction on the emergence of neurological deficits.
Insights
Mitochondrial DNA (mtDNA) point mutations can impair spatial navigation in mice. Complex I dysfunction is linked to neurological deficits, suggesting a role for mtDNA defects in cognitive decline.
Area of Science:
- Mitochondrial biology
- Neuroscience
- Genetics
Background:
- Large-scale mitochondrial DNA (mtDNA) defects negatively impact lifespan and cause tissue loss.
- The functional consequences of homoplasmic mtDNA point mutations, particularly in electron transport chain genes, are debated.
Purpose of the Study:
- To investigate the impact of specific homoplasmic mtDNA point mutations on cognitive function and reactive oxygen species (ROS) production.
- To explore the role of ontogenetic development in mtDNA mutation-related phenotypes.
Main Methods:
- Utilized a mouse model with a specific point mutation in complex I of the respiratory chain.
- Assessed spatial navigation using the Morris Water Maze in adolescent mice.
- Measured reactive oxygen species (ROS) production in juvenile and adolescent mice.
Main Results:
- A single point mutation in complex I impaired spatial navigation in adolescent mice.
- Increased ROS production was observed in juvenile mice with the complex I mutation, but not at the age of phenotype expression.
- A complex III point mutation showed only mild, non-significant effects on cognition and no significant changes in ROS.
Conclusions:
- Specific mtDNA point mutations, particularly in complex I, can lead to neurological deficits such as impaired spatial navigation.
- The developmental stage is crucial for observing mtDNA mutation phenotypes, with ROS production potentially preceding cognitive impairment.
- Complex I dysfunction is a potential contributor to the development of neurological deficits.
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