Embryonic Depletion of D-Aspartate Perturbs NMDA Receptor-Dependent Long-Term Potentiation in the Hippocampus of Juvenile Mice.

D-Aspartate (D-Asp) is an endogenous NMDA receptor agonist that exhibits a pronounced developmental peak in the mammalian brain, suggesting a regulatory role in glutamatergic signaling and neurodevelopment. Disruption of D-Asp homeostasis has been associated with neuropsychiatric disorders characterized by early-life circuit vulnerability, including schizophrenia and autism spectrum disorders. However, its impact on hippocampal physiology remains incompletely defined. Here, we investigated how constitutive D-Asp depletion affects synaptic function in the hippocampal CA1 region of Ddo-knock-in (Ddo-KI) mice, in which zygotic overexpression of the D-Asp-degrading enzyme, D-aspartate oxidase (DDO or DASPO), results in embryonic and persistent D-Asp deficiency. Electrophysiological recordings were performed in acute hippocampal slices from male and female mice at postnatal Day 30 (P30) and Day 60 (P60). Analysis of basal synaptic transmission, assessed through paired-pulse ratio and spontaneous excitatory/inhibitory events, revealed no significant genotype-dependent differences. In contrast, NMDA receptor (NMDAR)-dependent synaptic plasticity was selectively altered, as theta-burst stimulation induced significantly greater long-term potentiation (LTP) in juvenile P30 Ddo-KI mice. This paradoxical enhancement was no longer observed at P60, indicating that the phenotype is developmentally restricted. Patch-clamp recordings further revealed a reduced AMPAR/NMDAR ratio in P30 Ddo-KI males, suggesting an altered balance between AMPAR- and NMDAR-mediated synaptic currents. Importantly, acute bath application of exogenous D-Asp rapidly restored LTP to wild-type levels, indicating that the electrophysiological phenotype is acutely reversible and sensitive to D-Asp availability. Biochemical analyzes confirmed increased DASPO activity and reduced D-Asp levels in Ddo-KI mice at both ages examined, indicating that the age-dependent plasticity phenotype is unlikely to result from age-dependent changes in D-Asp catabolism. Overall, these findings demonstrate that early developmental D-Asp deficiency induces a paradoxical, juvenile-specific enhancement of hippocampal NMDAR-dependent synaptic plasticity, highlighting the importance of D-Asp homeostasis during brain development.