Limits...
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

LTP levels of mtALR, mt129S1 and control strains at the age of 6 months.(A) Time course of field excitatory postsynaptic potentials (fEPSP) measured in Schaffer collateral-CA1 synapses from mtALR (n = 6 slices / 4 animals), mt129S1 (n = 9 slices / 5 animals), and control strains BL6 (n = 5 slices / 4 animals) and mtAKR (n = 18 slices / 13 animals). Each circle represents the percentage of fEPSP slope relative to mean baseline value. Following a 10 min baseline recording, three times of theta-burst stimulation protocol (TBS) was delivered at time point 0 indicated by black arrow. Superimposed traces above show representative fEPSPs from each strain before and 55 min after TBS. (B) Bar graphs show mean values of LTP, calculated between minute 55 and minute 60 after TBS stimulation relative to baseline. Both, mtALR and mt129S1 did not show any significant differences in LTP levels compared to control strains. Diamonds (◊) show statistical significance of LTP level relative to baseline (p < 0.05). All mean values are presented with error bars (± SEM).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4390344&req=5

pone.0123863.g002: LTP levels of mtALR, mt129S1 and control strains at the age of 6 months.(A) Time course of field excitatory postsynaptic potentials (fEPSP) measured in Schaffer collateral-CA1 synapses from mtALR (n = 6 slices / 4 animals), mt129S1 (n = 9 slices / 5 animals), and control strains BL6 (n = 5 slices / 4 animals) and mtAKR (n = 18 slices / 13 animals). Each circle represents the percentage of fEPSP slope relative to mean baseline value. Following a 10 min baseline recording, three times of theta-burst stimulation protocol (TBS) was delivered at time point 0 indicated by black arrow. Superimposed traces above show representative fEPSPs from each strain before and 55 min after TBS. (B) Bar graphs show mean values of LTP, calculated between minute 55 and minute 60 after TBS stimulation relative to baseline. Both, mtALR and mt129S1 did not show any significant differences in LTP levels compared to control strains. Diamonds (◊) show statistical significance of LTP level relative to baseline (p < 0.05). All mean values are presented with error bars (± SEM).

Mentions: As a next step, we investigated whether hippocampal synaptic plasticity, thought to reflect learning mechanisms, might be affected, since e.g. chemically induced mitochondrial defects (blockade of voltage-dependent anion channels) show a reduction in hippocampal LTP [32]. Surprisingly, LTP induced by theta-burst stimulation of CA1 pyramidal cells via Schaffer-collateral activation did not show any difference between strains, although LTP could successfully be induced in all mutants (Fig 2). Thus, no significant differences appeared among mtALR (141 ± 5%), mt129S1 (164 ± 9%) and control strains BL6 (140 ± 7%) and mtAKR (151 ± 9%) regarding expression of LTP. Hence, learning performance and LTP are apparently only indirectly correlated, and at least under mitochondrial functional challenge, may show divergent behavior.


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)

LTP levels of mtALR, mt129S1 and control strains at the age of 6 months.(A) Time course of field excitatory postsynaptic potentials (fEPSP) measured in Schaffer collateral-CA1 synapses from mtALR (n = 6 slices / 4 animals), mt129S1 (n = 9 slices / 5 animals), and control strains BL6 (n = 5 slices / 4 animals) and mtAKR (n = 18 slices / 13 animals). Each circle represents the percentage of fEPSP slope relative to mean baseline value. Following a 10 min baseline recording, three times of theta-burst stimulation protocol (TBS) was delivered at time point 0 indicated by black arrow. Superimposed traces above show representative fEPSPs from each strain before and 55 min after TBS. (B) Bar graphs show mean values of LTP, calculated between minute 55 and minute 60 after TBS stimulation relative to baseline. Both, mtALR and mt129S1 did not show any significant differences in LTP levels compared to control strains. Diamonds (◊) show statistical significance of LTP level relative to baseline (p < 0.05). All mean values are presented with error bars (± SEM).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390344&req=5

pone.0123863.g002: LTP levels of mtALR, mt129S1 and control strains at the age of 6 months.(A) Time course of field excitatory postsynaptic potentials (fEPSP) measured in Schaffer collateral-CA1 synapses from mtALR (n = 6 slices / 4 animals), mt129S1 (n = 9 slices / 5 animals), and control strains BL6 (n = 5 slices / 4 animals) and mtAKR (n = 18 slices / 13 animals). Each circle represents the percentage of fEPSP slope relative to mean baseline value. Following a 10 min baseline recording, three times of theta-burst stimulation protocol (TBS) was delivered at time point 0 indicated by black arrow. Superimposed traces above show representative fEPSPs from each strain before and 55 min after TBS. (B) Bar graphs show mean values of LTP, calculated between minute 55 and minute 60 after TBS stimulation relative to baseline. Both, mtALR and mt129S1 did not show any significant differences in LTP levels compared to control strains. Diamonds (◊) show statistical significance of LTP level relative to baseline (p < 0.05). All mean values are presented with error bars (± SEM).
Mentions: As a next step, we investigated whether hippocampal synaptic plasticity, thought to reflect learning mechanisms, might be affected, since e.g. chemically induced mitochondrial defects (blockade of voltage-dependent anion channels) show a reduction in hippocampal LTP [32]. Surprisingly, LTP induced by theta-burst stimulation of CA1 pyramidal cells via Schaffer-collateral activation did not show any difference between strains, although LTP could successfully be induced in all mutants (Fig 2). Thus, no significant differences appeared among mtALR (141 ± 5%), mt129S1 (164 ± 9%) and control strains BL6 (140 ± 7%) and mtAKR (151 ± 9%) regarding expression of LTP. Hence, learning performance and LTP are apparently only indirectly correlated, and at least under mitochondrial functional challenge, may show divergent behavior.

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