Trends in Neurosciences
Reviewd-Serine signalling in the brain: friend and foe
Introduction
Classically, chemical synapses are viewed as polarized elements, and neurotransmitters are seen as neuron-derived substances that are released upon depolarization of the nerve terminal and bind to specific receptors on the postsynaptic target cell. However, the CNS is made up of neurons and glia, with glia being by far the more numerous. In an ascending phylogenic scale, the numeric preponderance of glia over neurons is already notable in rodents, greatly increases in primates and reaches its peak in humans with a 4:1 ratio [1]. Glia are well positioned to communicate with neurons at synapses, where chemical communication occurs via their fine processes that are in close proximity to synapses [2]. Over the past decade, it has become evident that this intimate structural relationship is the locus of bidirectional communication between neurons and glia 3, 4. Thus, the emerging concept of the tripartite synapse considers astrocytes as dynamic partners of neurons at synapses, controlling synaptogenesis [5] and synaptic transmission [6]. Astrocytes are thought to control these processes by sensing the level of synaptic activity and, in turn, influencing synaptic activity by the regulated release of neuromodulators 3, 4. Although glutamate and ATP are the most well known ‘gliotransmitters’ mediating this astrocyte–neuron crosstalk, it is now obvious that d-serine, another amino acid, can be added to the list [7]. The discovery of d-serine in the CNS revolutionised our thinking and forced us to reconsider the long cherished dogma that only l-isomers of amino acids occur in mammalian tissues and body fluids. The present review highlights the most recent findings about the molecular mechanisms controlling d-serine availability in the brain, which have led to the discovery that this atypical messenger not only has a vital role in promoting neuronal migration and synaptic plasticity but also behaves as a pro-death signal during excitotoxic and neuroinflammatory insults.
Section snippets
How does the CNS make and degrade d-serine?
Little attention was paid to d-serine function in the CNS until the identification of the glial pyridoxal 5′-phosphate (PLP)-dependent serine racemase (SR) [8]. This enzyme directly converts l-serine into d-serine, l-serine being the only source for endogenous d-serine in the brain. SR also converts d-serine into l-serine, albeit with lower affinity. Different genes for SR have been identified in mice, rats and humans 9, 10, 11 (Figure 1a). The distribution of SR is very similar to that
How do astrocytes regulate synaptic d-serine?
As yet, there is no consensus about how astrocytes regulate d-serine levels at synapses. Pioneer experiments conducted on astrocytes in culture revealed that activation of non-NMDA receptors, notably AMPA/kainate subtype glutamate receptors, is the main stimulus triggering the efflux of d-serine from these cells [27] (Figure 2). However, we still do not know whether this occurs in vivo. In the rat striatum for example, no changes in d-serine extracellular concentrations were noted in response
d-Serine, an active modulator of synaptic transmission
A key advance in our appreciation of the role of d-serine in the CNS derives from observations that d-serine is found in astrocytes that ensheathe NMDA-receptor-bearing neurons and that levels of d-serine parallel the ontogeny of these receptors 33, 47. In vitro studies teach us that d-serine is released from astrocytes upon activation of their glutamatergic receptors [27]. All these observations strongly suggest that, in some regions of the brain, glutamate released from the nerve terminal
d-Serine, a motility-promoting signal during development
Radial migration of immature granule cells in the developing cerebellum is one of the best-characterized instances of the participation of NMDA receptors in neuronal migration [58]. As they migrate through the molecular layer, immature neurons are guided by Bergmann glia (Figure 3). Real-time observation of cell migration in acute cerebellar slices revealed that glutamate, acting on NMDA receptors, has a crucial, modulatory effect on promoting the motility of granule cells through the molecular
But, d-serine, a pro-death signal
Should we conclude that d-serine is a good Samaritan that subtly regulates NMDA receptor activity? It is well known that NMDA receptors can cause cell death in many neuropathological conditions when they are intensely or chronically activated 66, 67, 68. Increased extracellular levels of glutamate, resulting from downregulation of its uptake system [69] or from active release [70], are the primary cause of neuronal death following excessive NMDA receptor activation [68]. Because d-serine
Concluding remarks
Recent literature has unveiled multiple roles for d-serine in the brain. This atypical amino acid can serve as a gliotransmitter that modulates neurotransmission at glutamatergic synapses, and is a motility-promoting signal important for development and maturation of the CNS. However, it can also cause cell death when in excess, through overactivation of NMDA receptors in neuropathological conditions. The features of d-serine activity thus parallel those of NMDA receptors. Of course, many
Acknowledgements
We thank Drs Dionysia Theodosis and Elisabeth Traiffort for graciously providing critical readings of the manuscript. We also acknowledge Lydie Collet and Marielle Rimard for their technical assistance in preparing the figures. We apologize to those whose work we were unable to cite owing to space limitations. J.P.M. is supported by grants from the CNRS and Servier laboratories. M.M. is a recipient of a PhD fellowship from the ‘Ministère de l’Enseignement, de la Recherche et de la Technologie’.
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