Prenatal and Early Postnatal Cerebral d-Aspartate Depletion Influences l-Amino Acid Pathways, Bioenergetic processes, and Developmental Brain Metabolism

Abstract

D-Amino acids were believed to occur only in bacteria and invertebrates. Today, it is well known that D-amino acids are also present in mammalian tissues in a considerable amount. In particular, high levels of free D-serine (D-Ser) and Daspartate (D-Asp) are found in the brain. While the functions of D-Ser are well known, many questions remain unanswered regarding the role of D-Asp in the central nervous system. D-Asp is very abundant at the embryonic stage, while it strongly decreases after birth because of the expression of D-aspartate oxidase (Ddo) enzyme, which catalyzes the oxidation of this D-amino acid into oxaloacetate, ammonium, and hydrogen peroxide. Pharmacologically, D-Asp acts as an endogenous agonist of N-methyl D-aspartate and mGlu5 receptors, which are known to control fundamental brain processes, including brain development, synaptic plasticity, and cognition. In this work, we studied a recently generated knockin mouse model (R26 Ddo/Ddo ), which was designed to express DDO beginning at the zygotic stage. This strategy enables D-Asp to be almost eliminated in both prenatal and postnatal lives. To understand which biochemical pathways are affected by depletion of D-Asp, in this study, we carried out a metabolomic and lipidomic study of Ddo knockin brains at different stages of embryonic and postnatal development, combining nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) techniques.Our study shows that D-Asp deficiency in the brain influences amino acid pathways such as threonine, glycine, alanine, valine, and glutamate. Interestingly, D-Asp is also correlated with metabolites involved in brain development and functions such as choline, creatine, phosphocholine (PCho), glycerophosphocholine (GPCho), sphingolipids, and glycerophospholipids, as well as metabolites involved in brain energy metabolism, such as GPCho, glucose, and lactate.

Influence of Maternal Immune Activation and Stressors on the Hippocampal Metabolome

“…Increased aspartate and glutamate levels were detected in the hippocampi of seven-week-old rats experiencing sleep fragmentation stress relative to controls [ 60 ]. Moreover, a metabolome study of the whole brain in mice concluded that aspartate deficiency influences alanine, valine, glutamate, threonine, and glycine amino acid pathways [ 61 ]. The aspartate profile was correlated with metabolites that participate in brain development and function, including choline and creatine, and in brain energy metabolism, including glucose and lactate.…”

Targeted metabolite profiling of Salvia rosmarinus Italian local ecotypes and cultivars and inhibitory activity against Pectobacterium carotovorum subsp. carotovorum

“…Quantitative analysis of NMR spectra was performed using NMRProcFlow 1.4.14 (INRA UMR 1332 BFP, Bordeaux Metabolomics Facility, Villenave d’Ornon, France) ( Jacob et al., 2017 ) following the method reported by Grimaldi et al. ( Grimaldi et al., 2021 ). Briefly, corrections of phasing and baseline were performed manually for all spectra using TOPSPIN version 3.2.…”

NMR Metabolite Profiling for the Characterization of Vessalico Garlic Ecotype and Bioactivity against Xanthomonas campestris pv. campestris

“…NMR data were acquired on a Bruker. NMR spectra analysis and metabolite quantification were then performed by using the online server NMRProcFlow (INRA UMR 1332 BFP, Bordeaux Metabolomics Facility, Villenave d'Ornon, France) [116] following the method reported by Grimaldi et al [117]. Briefly, corrections of phasing and baseline were performed manually for all spectra using TOPSPIN version 3.2.…”