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Metabolomic profiling reveals a differential role for hippocampal glutathione reductase in infantile memory formation.

ABSTRACT: The metabolic mechanisms underlying the formation of early-life episodic memories remain poorly characterized. Here, we assessed the metabolomic profile of the rat hippocampus at different developmental ages both at baseline and following episodic learning. We report that the hippocampal metabolome significantly changes over developmental ages and that learning regulates differential arrays of metabolites according to age. The infant hippocampus had the largest number of significant changes following learning, with downregulation of 54 metabolites. Of those, a large proportion was associated with the glutathione-mediated cellular defenses against oxidative stress. Further biochemical, molecular, and behavioral assessments revealed that infantile learning evokes a rapid and persistent increase in the activity of neuronal glutathione reductase, the enzyme that regenerates reduced glutathione from its oxidized form. Inhibition of glutathione reductase selectively impaired long-term memory formation in infant but not in juvenile and adult rats, confirming its age-specific role. Thus, metabolomic profiling revealed that the hippocampal glutathione-mediated antioxidant pathway is differentially required for the formation of infantile memory.

SUBMITTER: Bessieres B

PROVIDER: S-EPMC8626085 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The ascorbate-glutathione cycle is a metabolic pathway that detoxifies hydrogen peroxide and involves enzymatic and non-enzymatic antioxidants. Proteomic studies have shown that some enzymes in this cycle such as ascorbate peroxidase (APX), monodehydroascorbate reductase (MDAR), and glutathione reductase (GR) are potential targets for post-translational modifications (PMTs) mediated by nitric oxide-derived molecules. Using purified recombinant pea peroxisomal MDAR and cytosolic and chloroplastic GR enzymes produced in Escherichia coli, the effects of peroxynitrite (ONOO(-)) and S-nitrosoglutathione (GSNO) which are known to mediate protein nitration and S-nitrosylation processes, respectively, were analysed. Although ONOO(-) and GSNO inhibit peroxisomal MDAR activity, chloroplastic and cytosolic GR were not affected by these molecules. Mass spectrometric analysis of the nitrated MDAR revealed that Tyr213, Try292, and Tyr345 were exclusively nitrated to 3-nitrotyrosine by ONOO(-). The location of these residues in the structure of pea peroxisomal MDAR reveals that Tyr345 is found at 3.3 Å of His313 which is involved in the NADP-binding site. Site-directed mutagenesis confirmed Tyr345 as the primary site of nitration responsible for the inhibition of MDAR activity by ONOO(-). These results provide new insights into the molecular regulation of MDAR which is deactivated by nitration and S-nitrosylation. However, GR was not affected by ONOO(-) or GSNO, suggesting the existence of a mechanism to conserve redox status by maintaining the level of reduced GSH. Under a nitro-oxidative stress induced by salinity (150mM NaCl), MDAR expression (mRNA, protein, and enzyme activity levels) was increased, probably to compensate the inhibitory effects of S-nitrosylation and nitration on the enzyme. The present data show the modulation of the antioxidative response of key enzymes in the ascorbate-glutathione cycle by nitric oxide (NO)-PTMs, thus indicating the close involvement of NO and reactive oxygen species metabolism in antioxidant defence against nitro-oxidative stress situations in plants.

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Metabolomic profiling reveals a differential role for hippocampal glutathione reductase in infantile memory formation.

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