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• Overview

  D-serine is the D-form of the amino acid serine, but is not used for the protein synthesis. Amino acids are among the most significant molecules in nature and exist in an l- and a d-form. The chemical and physical properties of l- and d-amino acids are enormously similar except for their optical characteristics^[1]. During the emergence of life, only the l-amino acids were selected for the formation of polypeptides and proteins. Amino acids are not present in mammals and that d-amino acids were restricted to some bacteria and insects. Only a few decades ago, it was largely believed that free d- amino acids are not present in mammals and that d-amino acids were restricted to some bacteria and insects. Often, d-amino acids were called “unnatural” amino acids and they were considered to be the by-products of microorganisms metabolism.
  The first report to show the presence of substantial quantities of free d-amino acids in mammalian tissues was by dunlop et al 1986 where, surprisingly, a large amount of d-aspartic acid[d- asp] in the cerebrum of a newborn rat and in the pituitary gland of an adult rat was reported^[2]. A second d-amino acid, d-serine, was then identified in considerable amounts in the brains of rodents and man^{[3, 4]}. Successive studies verified that some d- amino acids exist in the mammalian central nervous system(CNS) and peripheral tissues in, unpredictably, high concentrations that may exceed the level of l-amino acids occurrence^[4]. The unanticipated detection of large amounts of endogenous d-serine in the brain, by hashimoto et al, initiated a series of studies from several laboratories that investigated the physiological role of endogenous d-serine. Recently endogenous d-serine has been associated with several physiological and pathological n-methyl-d-aspartate receptor(NMDAR)-reliant processes, including NMDAr transmission and synaptic plasticity^[5-7], cell migration, and neurotoxicity^[8-10].
  
  Figure 1 the chemical structure of D-serine;

• Localization

  The distribution of d-serine is parallel to the distribution of nMda type glutamate receptors^[4]. D-Serine has been detected at relatively high levels in certain areas in the adult brain with particularly high levels of nMdars, including cerebral cortex, hippocampus, thalamus, hypothalamus, amygdala, and retina. Nonetheless, brain regions, such as the hindbrain, pons, and medulla have nearly imperceptible levels of d-serine. Significantly, it has been demonstrated that d-serine is localized principally within glial cells^{[14, 5]} in the retina, Stevens et al^[4] reported the occurrence of d-serine in astrocytes and Mu?ller glia cells. Recently, several studies suggest that the synthesis, storage, and release of d-serine may not be limited exclusively to astrocytes, but rather may involve specific functions for certain cells^[6]. ;

• Synthesis and Metabolism

  Humans can acquire D-serine through ingestion with food, derivation from gastrointestinal bacteria, liberation from metabolically stable proteins, which contain D-amino acids after racemization with ageing, and through biosynthesis from L-serine. Few data are available on the relative contributions of these four sources, but biosynthesis appears to be important. The enzyme serine racemase(SR) directly converts Lto D-serine in the presence of the co-factors pyridoxal 5-phosphate, magnesium and ATP^[15-17]. SR also converts Dto L-serine, albeit with lower affinity^[17]. D-Serine concentrations are thus highly related to L-serine concentration and thereby also to glycine concentrations^[18]. Of the different pathways involved in L-serine biosynthesis, the glucose– 3-phosphoglycerate-3-phosphoserine–biosynthesis pathway is essential for normal embryonic development, especially for brain morphogenesis.^[19] Consequently, D-serine concentrations in the developing CNS might also depend heavily on this pathway.
  SR is highly expressed in the brain, with lower levels in the liver and small or no detectable expression in other tissues. In the brain, SR localizes to protoplasmic astrocytes in a pattern similar to D-serine.^[16,17] Physiological synthesis of D-serine by SR in the glia was implicated by the strong spatiotemporal correlation between D-serine and SR^[20] and by the decrease in D-serine concentrations in astrocytes after pharmacological inhibition of SR.^[16] The cDNA encoding human SR has been cloned and D-serine synthesis by SR has been demonstrated in living cells after heterologous overexpression.^[21] Whereas human serine hydratase does not contribute substantially to the degradation of L-serine to pyruvate, SR was found to catalyze, in addition to the racemase activity, the α,β-elimination of water from both L-serine and D-serine to form pyruvate and ammonia.^[15,22] Under physiological conditions, pyruvate formation seems to equal or excess Dserine formation. Pyruvate formed by SR may be sufficient for the energy requirements of the astrocytes. This reaction further implies that SR is not only involved in D-serine synthesis, but also in D-serine metabolism as a mechanism to regulate intracellular Dserine levels.^[22] Mammalian D-amino acids can be metabolized by the peroxisomal flavoprotein DAO, with the concomitant reduction of the co-factor flavin adenine dinucleotide(FAD). Physiological degradation of D-serine by DAO was suggested by the marked regional and developmental variation in DAO levels in a pattern reciprocal to D-serine levels.^[20] Furthermore, Dao-/mice manifest an increase in D-serine levels, especially in areas with low levels in wild type animals such as the cerebellum and periphery^[24]. The relatively unchanged D-serine levels in the forebrains of DAO-/mice imply that in these areas, other mechanisms might regulate D-serine concentrations^[24,25]. ;

• Biological effects

  NMDAr neurotransmission
  The evident association between the anatomical distribution of d-serine and the localization of the NMDAr suggests a functional relationship. NMDArs are largely distributed throughout the CNS and play a major role in glutamatergic synaptic transmission^[26]. NMDArs are tetrameric ionotropic receptor channels that are major excitatory receptors in the brain; they play various roles in different physiological processes, such as nMda transmission, synaptic plasticity, and development^[26].
  Functional evidence for the contribution of endogenous D-serine to physiological nMdar co-activation was reported in a pioneer study by Mothet et al. in this study, addition of DAO, an enzyme that selectively degrades d-amino acids but not l-amino acids, to neural cell cultures resulted in depletion of endogenous d-serine and eventually noticeable reduction in nMdar activity^[7]. This effect was fully reversed by the application of exogenous d-serine[7]. Subsequent studies demonstrated that endogenous d-serine is required for nMdar mediated lightevoked responses in the vertebrate retina^{[5, 11]}.
  NMDArs play a major role in excitatory transmission and synaptic plasticity, such as long-term potentiation(LTP)^[28]. D-Serine contribution to activity-induced synaptic plasticity was further confirmed when yang et al compared the ability to evoke LTP in cultured neurons between cells grown in direct contact with astrocytes and those grown without direct contact. Surprisingly, neurons that were not in direct contact with astrocytes failed to induce LTP. When the cells were supplemented with an exogenous source of d-serine, LTP was successfully induced^[27]. Similarly, the contribution of d-serine to activity-induced synaptic plasticity in other brain areas, such as the hypothalamus, retina, and prefrontal cortex has been confirmed^{[12, 29, 30]}.
  CNS development
  The noticeably elevated d-serine concentrations in human and rodent CNS 4, 26 during the intense stage of embryonic and early postnatal CNS development provided the first evidence for a specific role for d-serine in CNS development. Supportive to this role, elevated d-serine concentrations coincide with transient expression^[31] and increased activity^[32-34] of nMdars. Likewise, Fuchs et al reported the presence of high d-serine concentrations in human cerebrospinal fluid(CSF) during the early postnatal period^[35]. Moreover, excessive levels of d-serine have been detected in the cerebellum of neonatal rats, decreasing to very low levels in the third week of life as a result of the emergence of dao26. This temporary abundance of d-serine in the cerebellum corresponds with postnatal cerebellar development, in which granule cells migrate from the external to the internal granule cell layer in an nMdar-dependent manner^[36]. Moreover, it has been shown that d-serine appears to be engaged in neuronal migration. DAO catalyzed degradation of d-serine and selective inhibition of Sr in eight day-old mouse cerebellar slices considerably suppressed granule cell migration, while d-serine appears to activate the migration through nMdar activation^[36]. Supportive evidence for the d-serine role in migration is provided by the definite mass spectrometric identification of SR in the perireticular nucleus, a short-lived structure of the developing brain in humans proposed to be largely involved in neuronal migration^[37].
  Learning and memory
  Long-term potentiation(LTP) of synaptic transmission in the hippocampus is broadly considered as one of the key cellular mechanisms underlying learning and memory in vertebrates96. It refers to an augmentation in signal transmission between neurons upon synchronic stimulation and is one of the fundamental processes of synaptic plasticity. D-Serine released from astrocytes and nMdar activation both appears to play a role in LTP induction. On the other hand, nMdar antagonists and enzymatic d-serine degradation suppressed LTP induction27. Further support provided from studies on SR knockout mice, where it had been shown that depletion of d-serine concentrations was directly related to an impaired nMdar transmission and attenuated ltp^[38]. On the contrary, DAO knockout mice display high extracellular d-serine concentrations, improved NMDAr function, and enhanced hippocampal LTP^{[39, 40]}.
  Studies assessing learning and memory decline occurring with aging revealed that SR expression, d-serine concentrations, nMdar-mediated synaptic potentials, and LTP were all drastically decreased in Ca1 hippocampal slices from aged rats when compared with young rats, and were all restored by exogenous d-serine^{[6, 41]}. Similarly, hippocampal slices from a senescence-accelerated mouse model exhibited substantial and amplified LTP suppression with age, when compared to normal mice, which was overcome by D-serine supplementation. Collectively, these results strongly demonstrate the significance of d-serine for nMdar activation and subsequent LTP induction that underlies learning and memory. ;

• Relation with diseases

  As it is involved in nMdar neurotransmission in the brain, nMdar-dependent plasticity, and developmental processes, it is not astonishing that dysregulation of d-serine signaling might also be involved in several pathologies, including neuropsychiatric and neurodegenerative diseases related to nMdar dysfunction. Intense stimulation of nMdars has been associated with considerable number of acute and chronic neurodegenerative conditions, including stroke, epilepsy, polyneuropathies, chronic pain, amyotrophic lateral sclerosis(ALS), Parkinson’s disease(PD), Alzheimer’s disease(AD), and Huntington’s disease(HD)^[42]. ;

• References

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