Prenatal Exposure to Lipopolysaccharide or Valproate Leads to Abnormal Accumulation of the NMDA Receptor Agonist D-Aspartate in the Adolescent Rat Brain

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental psychiatric condition linked to glutamatergic neurotransmission disruption. Although endogenous D-serine and D-aspartate modulate glutamatergic N-methyl D-aspartate receptor (NMDAR) activity, their involvement in ASD remains elusive. We measured the levels of D-aspartate, D-serine, and other key neuroactive amino acids, and their direct precursors in brain regions, plasma, and feces of environmental ASD rat models prenatally exposed to lipopolysaccharide or valproate, both during adolescence and early adulthood, as well as in a genetic ASD model, the Fmr1-^Δexon8 rat. No significant changes were found in plasma and feces. Conversely, we observed a prominent accumulation of D-aspartate in several brain regions of lipopolysaccharide- and valproate-exposed rats, selectively during adolescence, while D-serine level variations were more limited. No significant amino acid changes were observed in the Fmr1-^Δexon8 rat brain. We also assayed the activity of the main enzymes involved in cerebral D-serine and D-aspartate metabolism, suggesting that their regulation extends beyond their metabolic enzymes. These findings highlight that prenatal environmental stressors disrupt D-amino acid levels selectively in ASD rat brains, emphasizing the role of early NMDAR dysfunction in ASD-related phenotypes.