New insights on the role of free d-aspartate in the mammalian brain
- 799 Downloads
Free d-aspartate (d-Asp) occurs in substantial amounts in the brain at the embryonic phase and in the first few postnatal days, and strongly decreases in adulthood. Temporal reduction of d-Asp levels depends on the postnatal onset of d-aspartate oxidase (DDO) activity, the only enzyme able to selectively degrade this d-amino acid. Several results indicate that d-Asp binds and activates N-methyl-d-aspartate receptors (NMDARs). Accordingly, recent studies have demonstrated that deregulated, higher levels of d-Asp, in knockout mice for Ddo gene and in d-Asp-treated mice, modulate hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory. Moreover, similarly to d-serine, administration of d-Asp to old mice is able to rescue the physiological age-related decay of hippocampal LTP. In agreement with a neuromodulatory action of d-Asp on NMDARs, increased levels of this d-amino acid completely suppress long-term depression at corticostriatal synapses and attenuate the prepulse inhibition deficits produced in mice by the psychotomimetic drugs, amphetamine and MK-801. Based on the evidence which points to the ability of d-Asp to act as an endogenous agonist on NMDARs and considering the abundance of d-Asp during prenatal and early life, future studies will be crucial to address the effect of this molecule in the developmental processes of the brain controlled by the activation of NMDARs.
Keywordsd-Amino acids N-methyl d-aspartate receptor Synaptic plasticity Learning and memory Sensorimotor gating
F. E. was supported by a grant from the Italian Ministero dell’Istruzione, dell’Università e della Ricerca. A.U. represents the Mariano Scippacercola Foundation.
Conflict of interest
The authors have no conflict of interest to declare.
- Bak LK, Schousboe A, Waagepetersen HS (2003) Characterization of depolarization-coupled release of glutamate from cultured mouse cerebellar granule cells using dl-threo-beta-benzyloxyaspartate (dl-TBOA) to distinguish between the vesicular and cytoplasmic pools. Neurochem Int 43:417–424PubMedCrossRefGoogle Scholar
- Errico F, Nistico R, Palma G, Federici M, Affuso A, Brilli E, Topo E, Centonze D, Bernardi G, Bozzi Y, D’Aniello A, Di Lauro R, Mercuri NB, Usiello A (2008b) Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility. Mol Cell Neurosci 37:236–246PubMedCrossRefGoogle Scholar
- Errico F, Nistico R, Napolitano F, Oliva AB, Romano R, Barbieri F, Florio T, Russo C, Mercuri NB, Usiello A (2011a) Persistent increase of d-aspartate in d-aspartate oxidase mutant mice induces a precocious hippocampal age-dependent synaptic plasticity and spatial memory decay. Neurobiol Aging 32:2061–2074PubMedCrossRefGoogle Scholar
- Errico F, Bonito-Oliva A, Bagetta V, Vitucci D, Romano R, Zianni E, Napolitano F, Marinucci S, Di Luca M, Calabresi P, Fisone G, Carta M, Picconi B, Gardoni F, Usiello A (2011c) Higher free d-aspartate and N-methyl-d-aspartate levels prevent striatal depotentiation and anticipate l-DOPA-induced dyskinesia. Exp Neurol 232:240–250PubMedCrossRefGoogle Scholar
- Hashimoto A, Nishikawa T, Oka T, Takahashi K, Hayashi T (1992a) Determination of free amino acid enantiomers in rat brain and serum by high-performance liquid chromatography after derivatization with N-tert.-butyloxycarbonyl-l-cysteine and o-phthaldialdehyde. J Chromatogr 582:41–48PubMedCrossRefGoogle Scholar
- Kanahara N, Shimizu E, Ohgake S, Fujita Y, Kohno M, Hashimoto T, Matsuzawa D, Shirayama Y, Hashimoto K, Iyo M (2008) Glycine and d: -serine, but not d: -cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801. Psychopharmacology 198:363–374PubMedCrossRefGoogle Scholar