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bioRxiv · 10.64898/2026.04.22.720120

Embryonic depletion of D-aspartate perturbs NMDA receptor-dependent long-term potentiation in the hippocampus of juvenile mice

Mango, D.·Errico, F.·Motta, Z.·Dashtiani, S.·Di Maio, A.·Nistico, R.·De Stefano, M. E.·Pollegioni, L.·Usiello, A.
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Abstract

D-Aspartate (D-Asp) is an endogenous D-amino acid that exhibits a pronounced developmental peak in the mammalian brain, suggesting a potential 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 functional impact to 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 (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). Basal synaptic transmission, assessed through paired-pulse ratio and spontaneous excitatory/inhibitory events, was unaltered between genotypes, indicating preserved presynaptic release probability and overall excitation/inhibition balance. 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, whereas this difference was no longer observed at P60. Consistently, patch-clamp recordings revealed a reduced AMPAR/NMDAR ratio in P30 Ddo-KI males, suggesting an increased relative contribution of NMDAR-mediated currents. Importantly, acute bath application of exogenous D-Asp restored LTP to wild-type levels, demonstrating rapid reversibility and supporting a model of homeostatic receptor rebalancing rather than irreversible circuit alterations. Biochemical assays confirmed significantly increased DASPO activity and reduced D-Asp levels in Ddo-KI mice. However, these parameters remained stable between P30 and P60, indicating that the age-dependent plasticity phenotype is unlikely to arise from progressive biochemical changes. Together, these findings indicate that developmental D-Asp deficiency induces a transient, juvenile-specific alteration characterized by enhanced NMDAR-dependent synaptic plasticity, which can be rapidly normalized upon D-Asp re-exposure.

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Mango, D., Errico, F., Motta, Z., Dashtiani, S., Di Maio, A., Nistico, R., De Stefano, M. E., Pollegioni, L., Usiello, A.. 2026-04-23. Embryonic depletion of D-aspartate perturbs NMDA receptor-dependent long-term potentiation in the hippocampus of juvenile mice. https://doi.org/10.64898/2026.04.22.720120

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