1. Hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function
- Author
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Juan P. Bolaños, Monica Carabias-Carrasco, Angeles Almeida, Silvia Gonzalez-Fernandez, Monica Resch, Joaquim Ros, Seila Fernandez-Fernandez, Raquel Requejo-Aguilar, Veronica Bobo-Jimenez, Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Junta de Castilla y León, Fundación Ramón Areces, Almeida, Angeles [0000-0003-0485-8904], and Almeida, Angeles
- Subjects
Male ,0301 basic medicine ,CK2a, calmodulin kinase 2A ,Clinical Biochemistry ,Hippocampus ,CA3, Cornu Ammonis area 3 ,In vivo knockdown ,Hippocampal formation ,Biochemistry ,DG, dendate gyrus ,chemistry.chemical_compound ,Cognition ,PCR, polymerase chain reaction ,0302 clinical medicine ,CA1, Cornu Ammonis area 1 ,shRNA, small hairpin RNA ,Cognitive decline ,lcsh:QH301-705.5 ,Neurons ,lcsh:R5-920 ,shGCLSFL, switched flox shGCL ,MEFs, mouse embryonic fibroblasts ,GlutathioneIn vivo knockdown ,GSSG, glutathione, oxidized form ,TUJ1, neuron-specific Class III β-tubulin ,Memory impairment ,Glutathione ,medicine.anatomical_structure ,shGCL, shRNA against GCL ,GSH, glutathione, reduced form ,lcsh:Medicine (General) ,Oxidation-Reduction ,Research Paper ,DMSO, dimethylsulfoxide ,SDS, sodium dodecyl sulfate ,MAP2, microtubule-associated protein-2 ,Dendrite ,shGCLUFL, unswitched flox shGCL ,Biology ,Glutamate-cysteine ligase ,03 medical and health sciences ,ROS, reactive oxygen species ,FBS, fetal bovine serum ,In vivo ,medicine ,Animals ,DTNB, 5,5′-dithio-bis-(2-nitrobenzoic acid) ,Redox stress ,DMEM, Dulbecco's modified Eagle's médium ,TM, 4-hydroxy-tamoxifen ,Organic Chemistry ,Dendrites ,Mice, Inbred C57BL ,GCL, glutamate-cysteine ligase, catalytic subunit ,Oxidative Stress ,030104 developmental biology ,chemistry ,nervous system ,lcsh:Biology (General) ,Dendrite disruption ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Loss of brain glutathione has been associated with cognitive decline and neuronal death during aging and neurodegenerative diseases. However, whether decreased glutathione precedes or follows neuronal dysfunction has not been unambiguously elucidated. Previous attempts to address this issue were approached by fully eliminating glutathione, a strategy causing abrupt lethality or premature neuronal death that led to multiple interpretations. To overcome this drawback, here we aimed to moderately decrease glutathione content by genetically knocking down the rate-limiting enzyme of glutathione biosynthesis in mouse neurons in vivo. Biochemical and morphological analyses of the brain revealed a modest glutathione decrease and redox stress throughout the hippocampus, although neuronal dendrite disruption and glial activation was confined to the hippocampal CA1 layer. Furthermore, the behavioral characterization exhibited signs consistent with cognitive impairment. These results indicate that the hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function., Graphical abstract fx1, Highlights • Whether glutathione fall precedes or follows neuronal dysfunction is unknown. • A genetic approach to downregulate glutathione in neurons in vivo was generated. • Systematic characterization reveals redox stress throughout the hippocampus. • Neuronal dendrite disruption was confined to neurons of the CA1 layer. • Behavioral characterization exhibits cognitive impairment.
- Published
- 2018