Hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function

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.

This work was funded by the MINECO, Spain (SAF2016-78114-R to JPB; Red de Excelencia CONSOLREDOX SAF2015-71521-REDC to JPB and JR), H2020 European Commission, Belgium (BatCure Grant 666918 to JPB; PANA grant 686009 to AA), Instituto de Salud Carlos III, Spain (CIBERFES CB16/10/00282 to JPB; PI15/00473 and RD16/ 0019/0018 to AA), Junta de Castilla y León, Spain (IES007P17) and Fundación Ramón Areces, Spain (to AA). This work was funded by FEDER, European Commission, Belgium.