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Reduced adolescent-age spatial learning ability associated with elevated juvenile-age superoxide levels in complex I mouse mutants.

Mayer J, Reichart G, Tokay T, Lange F, Baltrusch S, Junghanss C, Wolkenhauer O, Jaster R, Kunz M, Tiedge M, Ibrahim S, Fuellen G, Köhling R - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Oscar-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.

No MeSH data available.


Related in: MedlinePlus

Morris Water Maze performance in 6-month-old mice.Morris Water Maze performance of mtALR (n = 10) and mt129S1 (n = 10) versus control strains BL6 (n = 9) and mtAKR (n = 8). (A) Learning curves of 7 consecutive days (spatial acquisition). Data points represent mean values of escape latency of cohorts each day. Comparison of learning performance between mtALR, mt129S1 and control strains showed significantly higher values of escape latency in mtALR mice compared to both control strains. Bar graphs (B, C) show probe trial (8th day) carried out after acquisition phase. (B) Percentage of time spent in target-quadrant (TQ). Dashed line indicates assumed threshold of chance. No significant differences of percentage of time in target quadrant among strains and control were found. (C) Frequency of crossing target-zone definition (platform position). mtALR mice showed a lower frequency of target-zone crossing. All data shown as mean values ± SEM. Acquisition phase was analyzed for global differences using two-way RM ANOVA and post-hoc test Dunnett-T for inner-strain comparison. Asterisks (*) indicate statistical significance (*p < 0.05, **p < 0.01).
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pone.0123863.g001: Morris Water Maze performance in 6-month-old mice.Morris Water Maze performance of mtALR (n = 10) and mt129S1 (n = 10) versus control strains BL6 (n = 9) and mtAKR (n = 8). (A) Learning curves of 7 consecutive days (spatial acquisition). Data points represent mean values of escape latency of cohorts each day. Comparison of learning performance between mtALR, mt129S1 and control strains showed significantly higher values of escape latency in mtALR mice compared to both control strains. Bar graphs (B, C) show probe trial (8th day) carried out after acquisition phase. (B) Percentage of time spent in target-quadrant (TQ). Dashed line indicates assumed threshold of chance. No significant differences of percentage of time in target quadrant among strains and control were found. (C) Frequency of crossing target-zone definition (platform position). mtALR mice showed a lower frequency of target-zone crossing. All data shown as mean values ± SEM. Acquisition phase was analyzed for global differences using two-way RM ANOVA and post-hoc test Dunnett-T for inner-strain comparison. Asterisks (*) indicate statistical significance (*p < 0.05, **p < 0.01).

Mentions: Since mitochondrial structural decay and associated unspecific DNA/RNA oxidation have been found to be correlated to memory formation deficits [19], we hypothesized that also specific mtDNA mutations would have functional consequences for higher brain performance such as spatial learning, and that these should emerge in adolescent mice (6 months of age). This was indeed the case. During seven days of spatial acquisition phase, mice of the strain mtALR showed a significantly impaired performance finding a submerged platform in the MWM (Fig 1A). Thus, escape latency was increased by about 15 s during training session on days 2–7, compared to control strains. Two-way RM ANOVA with post-hoc Dunnett’s test showed these differences to be significant (p = 0.014) between mtALR and mtAKR, the mitochondrial background control strain; and highly significant (p = 0.001) between mtALR and BL6, the nuclear background control strain. Further, on the day of probe trial without a platform (day 8), mtALR mice spent less time (37.0 ± 4.6%) in the platform quadrant, albeit not significantly different from controls (BL6 44.4 ± 4.5%, mtAKR 43.6 ± 4.4%; Fig 1B). Analyzing the more accurate parameter of target crossing, a significant (p = 0.01) difference of target frequency emerged, as mtALR (1.1 ± 0.2) crossed the area definition less frequently than BL6 (2.1 ± 0.2; Fig 1C). These results suggest that complex I mutations can be instrumental in cognitive dysfunction.


Reduced adolescent-age spatial learning ability associated with elevated juvenile-age superoxide levels in complex I mouse mutants.

Mayer J, Reichart G, Tokay T, Lange F, Baltrusch S, Junghanss C, Wolkenhauer O, Jaster R, Kunz M, Tiedge M, Ibrahim S, Fuellen G, Köhling R - PLoS ONE (2015)

Morris Water Maze performance in 6-month-old mice.Morris Water Maze performance of mtALR (n = 10) and mt129S1 (n = 10) versus control strains BL6 (n = 9) and mtAKR (n = 8). (A) Learning curves of 7 consecutive days (spatial acquisition). Data points represent mean values of escape latency of cohorts each day. Comparison of learning performance between mtALR, mt129S1 and control strains showed significantly higher values of escape latency in mtALR mice compared to both control strains. Bar graphs (B, C) show probe trial (8th day) carried out after acquisition phase. (B) Percentage of time spent in target-quadrant (TQ). Dashed line indicates assumed threshold of chance. No significant differences of percentage of time in target quadrant among strains and control were found. (C) Frequency of crossing target-zone definition (platform position). mtALR mice showed a lower frequency of target-zone crossing. All data shown as mean values ± SEM. Acquisition phase was analyzed for global differences using two-way RM ANOVA and post-hoc test Dunnett-T for inner-strain comparison. Asterisks (*) indicate statistical significance (*p < 0.05, **p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4390344&req=5

pone.0123863.g001: Morris Water Maze performance in 6-month-old mice.Morris Water Maze performance of mtALR (n = 10) and mt129S1 (n = 10) versus control strains BL6 (n = 9) and mtAKR (n = 8). (A) Learning curves of 7 consecutive days (spatial acquisition). Data points represent mean values of escape latency of cohorts each day. Comparison of learning performance between mtALR, mt129S1 and control strains showed significantly higher values of escape latency in mtALR mice compared to both control strains. Bar graphs (B, C) show probe trial (8th day) carried out after acquisition phase. (B) Percentage of time spent in target-quadrant (TQ). Dashed line indicates assumed threshold of chance. No significant differences of percentage of time in target quadrant among strains and control were found. (C) Frequency of crossing target-zone definition (platform position). mtALR mice showed a lower frequency of target-zone crossing. All data shown as mean values ± SEM. Acquisition phase was analyzed for global differences using two-way RM ANOVA and post-hoc test Dunnett-T for inner-strain comparison. Asterisks (*) indicate statistical significance (*p < 0.05, **p < 0.01).
Mentions: Since mitochondrial structural decay and associated unspecific DNA/RNA oxidation have been found to be correlated to memory formation deficits [19], we hypothesized that also specific mtDNA mutations would have functional consequences for higher brain performance such as spatial learning, and that these should emerge in adolescent mice (6 months of age). This was indeed the case. During seven days of spatial acquisition phase, mice of the strain mtALR showed a significantly impaired performance finding a submerged platform in the MWM (Fig 1A). Thus, escape latency was increased by about 15 s during training session on days 2–7, compared to control strains. Two-way RM ANOVA with post-hoc Dunnett’s test showed these differences to be significant (p = 0.014) between mtALR and mtAKR, the mitochondrial background control strain; and highly significant (p = 0.001) between mtALR and BL6, the nuclear background control strain. Further, on the day of probe trial without a platform (day 8), mtALR mice spent less time (37.0 ± 4.6%) in the platform quadrant, albeit not significantly different from controls (BL6 44.4 ± 4.5%, mtAKR 43.6 ± 4.4%; Fig 1B). Analyzing the more accurate parameter of target crossing, a significant (p = 0.01) difference of target frequency emerged, as mtALR (1.1 ± 0.2) crossed the area definition less frequently than BL6 (2.1 ± 0.2; Fig 1C). These results suggest that complex I mutations can be instrumental in cognitive dysfunction.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Oscar-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.

No MeSH data available.


Related in: MedlinePlus