Normal mitochondrial respiratory function is essential for spatial remote memory in mice.
BACKGROUND
Mitochondrial DNA (mtDNA) with pathogenic mutations has been found in patients with cognitive disorders. However, little is known about whether pathogenic mtDNA mutations and the resultant mitochondrial respiration deficiencies contribute to the expression of cognitive alterations, such as impairments of learning and memory. To address this point, we used two groups of trans-mitochondrial mice (mito-mice) with heteroplasmy for wild-type and pathogenically deleted (Δ) mtDNA; the "low" group carried 50% or less ΔmtDNA, and the "high" group carried more than 50% ΔmtDNA.


RESULTS
Both groups had normal phenotypes for not only spatial learning, but also memory at short retention delays, indicating that ΔmtDNA load did not affect learning and temporal memory. The high group, however, showed severe impairment of memory at long retention delays. In the visual cortex and dentate gyrus of these mice, we observed mitochondrial respiration deficiencies, and reduced Ca²(+)/calmodulin-dependent kinase II-α (α-CaMKII), a protein important for the establishment of spatial remote memory.


CONCLUSIONS
Our results indicated that normal mitochondrial respiratory function is necessary for retention and consolidation of memory trace; deficiencies in this function due to high loads of pathogenically mutated mtDNA are responsible for the preferential impairment of spatial remote memory.
Tanaka
Daisuke
D
University of Tsukuba, Ibaraki, Japan. s0630475@ipe.tsukuba.ac.jp
Nakada
Kazuto
K
Takao
Keizo
K
Ogasawara
Emi
E
Kasahara
Atsuko
A
Sato
Akitsugu
A
Yonekawa
Hiromichi
H
Miyakawa
Tsuyoshi
T
Hayashi
Jun-Ichi
J
D000818:Animals; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D019069:Cell Respiration; D003071:Cognition / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics; D012153:Retention, Psychology / Q000502:physiology; D014793:Visual Cortex / Q000201:enzymology
D004272:DNA, Mitochondrial; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse