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Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis.

ABSTRACT: Cytochrome c (Cyt c), a heme-containing mitochondrial protein, has a critical function in both respiration and apoptosis. Consistent with these vital functions, somatic Cyt c mouse knockout is embryonic lethal. In order to investigate the sensitivity of postnatal neurons to Cyt c depletion, we developed a neuron-specific conditional knockout model. Neuron-specific Cyt c KO mouse (nCytcKO) was created by crossing the floxed Cyt c mouse with a CamKII?-cre transgenic mouse, which deletes the floxed alleles postnatally. nCytcKO mice were normal at birth but developed an abnormal phenotype starting at 8 weeks of age with weight loss, tremor, decreased sensorimotor coordination, and sudden death between 12 and 16 weeks. Histological analysis did not show major neuronal degeneration. Analyses of oxidative phosphorylation showed a specific reduction in complex IV levels. Markers of oxidative stress were also increased. This novel model showed that neuronal complex IV is destabilized in the absence of Cyt c. It also showed that ablation of Cyt c in neurons leads to severe behavioral abnormalities and premature death without detectable neuronal loss, suggesting that neurons have the potential to survive for extended periods of time without a functional OXPHOS.

SUBMITTER: Pinto M

PROVIDER: S-EPMC6942697 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis.

Pinto Milena M Vempati Uma D UD Diaz Francisca F Peralta Susana S Moraes Carlos T CT

Molecular neurobiology 20180906 5

Cytochrome c (Cyt c), a heme-containing mitochondrial protein, has a critical function in both respiration and apoptosis. Consistent with these vital functions, somatic Cyt c mouse knockout is embryonic lethal. In order to investigate the sensitivity of postnatal neurons to Cyt c depletion, we developed a neuron-specific conditional knockout model. Neuron-specific Cyt c KO mouse (nCytc<sup>KO</sup>) was created by crossing the floxed Cyt c mouse with a CamKIIα-cre transgenic mouse, which deletes ...[more]

PMID: 30191381

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Project description:Cognitive dysfunction occurs in many debilitating conditions including Alzheimer's disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity.We used constitutive and neuron-specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory.Constitutive Girk2-/- mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in gamma-aminobutyric acid neurons (GAD-Cre:Girk2flox/flox mice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal gamma-aminobutyric acid neurons but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII-Cre(+):Girk2flox/flox mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2flox/flox mice also displayed a selective impairment in contextual fear conditioning, as both cue fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/cornu ammonis 1 synapse in the dorsal hippocampus.Our data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders.

Dataset Information

Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis.

Publications

Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis.

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