Normal mitochondrial respiratory function is essential for spatial remote memory in mice

Daisuke Tanaka,Keizo Takao,Tsuyoshi Miyakawa,Emi Ogasawara,Atsuko Kasahara,Kazuto Nakada,Jun-Ichi Hayashi,Hiromichi Yonekawa,Akitsugu Sato

doi:10.1186/1756-6606-1-21

Abstract

BackgroundMitochondrial 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.ResultsBoth 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.ConclusionOur 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.

Highlights

Mitochondrial DNA with pathogenic mutations has been found in patients with cognitive disorders
Not all mito-mice are useful for examining cognitive alteration, because in mice with severe mitochondrial disease phenotypes due to high loads of ΔmtDNA, the abnormal cognitive function can be overshadowed by other abnormalities in the phenotype
The proportion of ΔmtDNA in various tissues of mito-mice increases progressively with aging, and the mice begin to show the onset of mitochondria-driven diseases other than those manifested cognitively [16]; we had to finish all of our behavioral analyses before ΔmtDNA accumulated to more than approximately 80%

Summary

Introduction

Mitochondrial DNA (mtDNA) with pathogenic mutations has been found in patients with cognitive disorders. 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. The remaining mitochondrial proteins for oxidative phosphorylation, metabolic enzymes, DNA and RNA polymerases, and ribosomal proteins are all encoded by the nuclear genome [1]. Mito-mice could provide direct evidence that mitochondrial respiration deficiencies induced by mtDNA accumulation are sufficient in themselves for expression of the clinical phenotypes observed in patients with mutated mtDNA

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