Jean-Pierre Mothet

Aix-Marseille Université | AMU · Centre de Recherche en Neurobiologie-Neurophysiologie de Marseille (UMR 7286 CRN2M)

D-Serine is an astrocyte-derived regulator for N-methyl-D-aspartate receptors, but the intracellular routes of its trafficking are still largely unknown. Here, we combined confocal microscopy with colocalization quantification to track the astrocytic organelles that store D-serine. We report that D-serine colocalizes with the transfected eGFP-synap...

Human genes coding for pLG72 and d-amino acid oxidase have recently been linked to the onset of schizophrenia. pLG72 was proposed as an activator of the human FAD-containing flavoprotein d-amino acid oxidase (hDAAO). In the brain this oxidizes d-serine, a potent activator of N-methyl-d-aspartate receptor. We have investigated the mechanistic regula...

D-serine is a glial neuromodulator that is linked to several brain disorders such as schizophrenia, epilepsy, or stroke. We have developed an in situ D-serine microbiosensor that consists in a cylindrical platinum microelectrode covered with a layer of D-amino acid oxidase from the yeast R. gracilis. This enzyme converts D-serine into hydroxypyruva...

NMDA receptors (NMDARs) are key glutamatergic receptors in the CNS. Their permeability to Ca2+ and their voltage-dependent Mg2+ block make them essential for synaptic transmission, synaptic plasticity, rhythmogenesis, gene expression and excitotoxicity. One very peculiar property is that their activation requires the binding of both glutamate and a...

d-Serine is an endogenous ligand for N-methyl-d-aspartate (NMDA) receptors, and alterations in its concentration have been related to several brain disorders, especially schizophrenia. It is therefore an important target neuromodulator for the pharmaceutical industry. To monitor d-serine levels in vivo, we have developed a microbiosensor based on c...

d-serine is now recognized as the main co-agonist for NMDA receptors. For years it was thought to be exclusively produced by astrocytes and was thus viewed as the archetype of gliotransmitters. Recent research have challenged this long cherished and appealing view by showing that in physiological conditions d-serine would rather originate from neur...

D-serine and glycine dose-response curves. Summary of Hill coefficient (nH), half maximal concentration (EC50) and n-values for the glycine/D-serine dose-response curves obtained on GluN2A- and GluN2B-NMDARs recombinants. p-Values (unpaired, two-tailed Student t-test) assess the difference between the EC50 obtained with D-serine and glycine. DOI: h...

Co-agonist and NMDAR-subunit developmental switch. Summary of the effects of BsGO, RgDAAO, Ro25-6981 and zinc normalized to baseline (mean ± s.e.m) in slices obtained from rats at indicated ages (see Figure 5—figure supplement 1). n values are indicated as well as p-values (paired Student t-test) assessing the significance of the effect achieved co...

Capillary electrophoresis measurements. Summary of the measurements of glutamate, glycine and D-serine content in slices at different ages. Values indicate average content (in nmoles per mg of tissue) ± s.e.m. p-Values indicate the level of significance (student t-test) between values in <P10 slices compared to values in adults. DOI: http://dx.doi....

The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for it...

Astrocytes are excitable neural cells that contribute to brain information processing via bidirectional communication with neurons. This involves the release of gliosignaling molecules that affect synapses patterning and activity. Mechanisms mediating the release of these molecules likely consist of non-vesicular and vesicular-based mechanisms. It...

The N-methyl d-aspartic acid receptors (NMDARs) are key glutamate receptors that transduce glutamatergic signals throughout the developing and adult central nervous system (CNS). Despite diversity in their subunit composition, their subcellular localization, and their biophysical and pharmacological properties, activation of NMDARs always requires...

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity. Their activation requires the binding of both glutamate and d-serine or glycine as co-agonist. The prevalence of either co-agonist on NMDA-receptor function differs between brain regions and remains undetermined in the visual cortex (VC) at the critical period of po...

NMDAR currents are antagonized by CPP and 7-Cl-KYN. A: Administration of the selective NMDARs antagonist CPP (1μM) expectedly abolished the recorded current, thus confirming their nature (n = 4). B: Bath application of the co-agonist site blocker 7-Cl-KYN decreased NMDA-EPSCs to the same extent as the selective D-serine scavenger D-amino acid oxida...

TBS induced depression depends on GlyRs and not NMDARs. A: The depression observed after TBS administration in the presence of glycine 100μM is not affected by the NMDAR co-agonist binding site blocker 7-Cl-KYN (50μM) indicating that putative regulation of NMDAR by glycine does not play a role in this process (n = 4). B: Instead, GlyRs underlie suc...

Astrocytes are housekeepers of the central nervous system (CNS) and are important for CNS development, homeostasis and defence. They communicate with neurones and other glial cells through the release of signalling molecules. Astrocytes secrete a wide array of classic neurotransmitters, neuromodulators and hormones, as well as metabolic, trophic an...

Although the extracellular serine protease tissue plasminogen activator (tPA) is involved in pathophysiological processes such as learning and memory, anxiety, epilepsy, stroke, and Alzheimer's disease, information about its regional, cellular, and subcellular distribution in vivo is lacking. In the present study, we observed, in healthy mice and r...

The N-Methyl D-Aspartic acid (NMDA) receptors (NMDAR) are key tetrameric ionotropic glutamate receptors that transduce glutamatergic signals throughout the central nervous system (CNS) and spinal cord. Although NMDARs are diverse in their subunit composition, subcellular localization and biophysical and pharmacological properties, their activation...

Glia plays an active role in neuronal functions and dysfunctions, some of which depend on the expression of astrocyte connexins, the gap junction channel and hemichannel proteins. Under neuroinflammation triggered by the endotoxin lipopolysacharide (LPS), microglia is primary stimulated and releases proinflammatory agents affecting astrocytes and n...

Significance NMDA receptors (NMDARs) support patterning and activity of synapses throughout life and are central to many brain disorders. The NMDAR activation requires the concomitant binding of glutamate and a coagonist glycine or d -serine. To date, whether a preference for one coagonist at specific connections occurs remains unsolved. Here, we s...

Accumulating evidence during the last decade established that D-serine is a key signaling molecule utilized by neurons and astroglia in the mammalian central nervous system. D-serine is increasingly appreciated as the main physiological endogenous coagonist for synaptic NMDA receptors at central excitatory synapses; it is mandatory for long-term ch...

Bone cancer pain is a common and disruptive symptom in cancer patients. In cancer pain animal models, massive reactive astrogliosis in the dorsal horn of the spinal cord has been reported. Since astrocytes may behave as driving partners for pathological pain, we investigated the temporal development of pain behavior and reactive astrogliosis in a r...

Unlock the D-serine Pandora’s box Fabrice Turpin, Queensland Brain institute, The University of Queensland, Australia. Jean-Pierre Mothet, Centre de recherche en Neurobiologie et Neurophysiologie de Marseille, Université Aix-Marseille, France. Jean-Marie Billard, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, France Amino aci...

Glial cells are increasingly recognized as active players that profoundly influence neuronal synaptic transmission by specialized signaling pathways. In particular, astrocytes have been shown recently to release small molecules, such as the amino acids L-glutamate and D-serine as "gliotransmitters," which directly control the efficacy of adjacent s...

N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and...

Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what...

The NMDA subtypes of glutamatergic receptors (NMDARs) are unusual in that their activation requires the binding of both glutamate and a co-agonist glycine or D-serine. Whereas glycine was first suggested to play such a role, it was later established that D-serine could serve as an endogenous co-agonist at different central synapses. We still do not...

N-methyl-D-aspartate receptors (NMDARs) subserve numerous neurophysiological and neuropathological processes in the cerebral cortex. Their activation requires the binding of glutamate and also of a coagonist. Whereas glycine and D-serine (D-ser) are candidates for such a role at central synapses, the nature of the coagonist in cerebral cortex remai...

Alterations in mechanisms that influence synaptic strength in the aging brain are proposed to underlie age-related deficits in memory encoding. Synaptic plasticity within neuronal networks of the central nervous system closely depends on the activation of the N-Methyl-D-Aspartate subtype of glutamate receptors (NMDA-R). In cerebral areas involved i...

An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits...

Alterations in mechanisms that influence synaptic strength in the aging brain are proposed to underlie age-related deficits in memory encoding. Synaptic plasticity within neuronal networks of the central nervous system closely depends on the activation of the N-Methyl-D-Aspartate subtype of glutamate receptors (NMDA-R). In cerebral areas involved i...

Activation of N-methyl-d-aspartate (NMDA) receptors (NMDARs) requires the binding of both glutamate and a co-agonist such as glycine or d-serine. There is a growing body of evidence indicating that d-serine, rather than glycine, is the endogenous ligand for NMDARs in many structures of the central nervous system. d-Serine is synthesized in glial ce...

To gain insight into the contribution of d-serine to impaired cognitive aging, we compared the metabolic pathway and content of the amino acid as well as d-serine-dependent synaptic transmission and plasticity in the hippocampus of young and old rats of the Wistar and Lou/C/Jall strains. Wistar rats display cognitive impairments with aging that are...

The adult hypothalamo-neurohypophysial system undergoes a striking activity-dependent morphological remodelling that modifies the glial enwrapping of its magnocellular neurons. Although the functional consequences of such remodelling remain hypothetical, recent evidence has provided new insights into the repercussions of glial environment modificat...

Although the chemical and physical properties of l-amino acids and d-amino acids are extremely similar, only l-amino acids seemed to have been selected from the origin of life on the primitive Earth. In their chemical evolutionary step, d-amino acids seemed to have been eliminated, and hence it has been considered that all superior living organisms...

Since the late 80s, it is recognized that functional activation of N-methyl D-aspartate receptors (NMDARs) requires the binding of both glutamate and glycine. However, the surprising discovery that the wrong isomer of serine, D-serine, is present in mammals has profoundly challenged this dogmatic model of NMDARs activation. Indeed, there are accumu...

Neurons and glia talk to each other at synapses. Glia sense the level of synaptic activity and consequently regulate its efficacy via the release of neuromodulators. One such glia-derived modulator is D-serine, an amino acid that serves as an endogenous ligand for the strychnine-insensitive glycine-binding site of NMDA glutamate receptors. Here, we...

The effects of the co-agonist of the N-methyl-D-aspartate receptor (NMDAr) D-serine on glutamatergic neurotransmission and synaptic potentiation were studied in the CA1 hippocampal field of young (3-5 months old) and aged (25-27 months old) Sprague-Dawley rats using ex vivo extracellular electrophysiological recording techniques. Exogenous d-serine...

The patterns of development of the vestibular nuclei (VN) and their main connections involving glutamate neurotransmission offer a good model for studying the function of the glial-derived neuromodulator D-serine in synaptic plasticity. In this study we show that D-serine is present in the VN and we analyzed its distribution and the levels of expre...

Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging,...

The NMDA receptor is a key player in excitatory transmission and synaptic plasticity in the central nervous system. Its activation requires the binding of both glutamate and a co-agonist like D-serine to its glycine site. As D-serine is released exclusively by astrocytes, we studied the physiological impact of the glial environment on NMDA receptor...

The patterns of development of the vestibular nuclei (VN) and their main connections involving glutamate neurotransmission offer a good model for studying the function of the glial-derived neuromodulator D-serine in synaptic plasticity. In this study we show that D-serine is present in the VN and we analyzed its distribution and the levels of expre...

Long ignored and only considered as housekeeping cells for neurons, astroglial cells in the last decade have gained increasing attention as key players of higher functions in healthy brain, but also in diseases. This revolution in our way to think the active brain culminates in the concept of a tripartite synapse, which considers glial cells and no...

Glutamate is the main neurotransmitter at the synapses between sensory cells and primary afferents in the peripheral vestibular system. Evidence has recently been obtained demonstrating that the atypical amino acid D-serine is the main endogenous co-agonist of the N-methyl-D-aspartate receptors in the CNS. We studied the distribution of D-serine an...

The gliotransmitter d-serine is released upon (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate and metabotropic glutamate receptor stimulation, but the mechanisms involved are unknown. Here, by using a highly sensitive bioassay to continuously monitor extracellular d-serine levels, we have investigated the pathways used in its relea...

D-Serine is an astrocyte-derived regulator for N-methyl-D-aspartate receptors, but the intracellular routes of its trafficking are still largely unknown. Here, we combined con-focal microscopy with colocalization quantification to track the astrocytic organelles that store D-serine. We report that D-serine colocalizes with the transfected eGFP-syna...

The gliotransmitter D-serine is released upon (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate and metabotropic glutamate receptor stimulation, but the mechanisms involved are unknown. Here, by using a highly sensitive bioassay to continuously monitor extracellular D-serine levels, we have investigated the pathways used in its r...

Over the last century, it has been considered that amino acids in mammalian tissues and body fluids occur solely in the l-configuration whether free or as components of peptides and proteins. However, the recent discovery that high levels of d-serine and d-aspartate are present in Mammals overturns this long-cherished theory. In this review, we foc...

Over the last century, it has been considered that amino acids in mammalian tissues and body fluids occur solely in the L-configuration whether free or as components of peptides and proteins. However, the recent discovery that high levels of D-serine and D-aspartate are present in Mammals overturns this long-cherished theory. In this review, we foc...

Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although D-serine is a more potent agonist. Localizations of D-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely tha...

Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endog-enous coagonist that has been presumed to be glycine, although D-serine is a more potent agonist. Localizations of D-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely th...

High levels of D-serine occur in mammalian brain, where it appears to be an endogenous ligand of the glycine site of N-methyl-D-aspartate receptors. In glial cultures of rat cerebral cortex, D-serine is enriched in type II astrocytes and is released upon stimulation with agonists of non-N-methyl-D-aspartate glutamate receptors. The high levels of D...

2,5-Diterbutyl-1,4-benzohydroquinone, a specific blocker of Ca2+-ATPase pumps, increased acetylcholine release from an identified synapse of Aplysia, as well as from Torpedo and mouse caudate nucleus synaptosomes. Because 2,5-diterbutyl-1,4-benzohydroquinone does not change the presynaptic Ca2+ influx, the enhancement of acetylcholine release could...

1. Presynaptic injection of cyclic ADP-ribose (cADPR), a modulator of the ryanodine receptor, increased the postsynaptic response evoked by a presynaptic spike at an identified cholinergic synapse in the buccal ganglion of Aplysia californica. 2. The statistical analysis of long duration postsynaptic responses evoked by square depolarizations of th...

Nitric oxide (NO) produced opposite effects on acetylcholine (ACh) release in identified neuroneuronal Aplysia synapses depending on the excitatory or the inhibitory nature of the synapse. Extracellular application of the NO donor, SIN-1, depressed the inhibitory postsynaptic currents (IPSCs) and enhanced the excitatory postsynaptic currents (EPSCs...

1. The exogenous nitric oxide (NO) donor, SIN-1, decreased the postsynaptic response evoked by a presynaptic spike at an identified cholinergic neuro-neuronal synapse in the buccal ganglion of Aplysia californica. 2. The statistical analysis of long duration postsynaptic responses evoked by square depolarizations of the voltage-clamped presynaptic...

The effects of nitric oxide on evoked acetylcholine (ACh) release were studied at two identified cholinergic neuro-neuronal synapses of the nervous system of the mollusc Aplysia californica. The NO-donor, 3-morpholinosydnonimine (SIN-1), decreased the amplitude of evoked inhibitory postsynaptic currents (buccal ganglion) and potentiated that of evo...

The role of nitric oxide or related molecules as neuromodulators was investigated in the buccal and the abdominal ganglia of the mollusc Aplysia californica. In a first step we showed that reduced nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry and specific nitric oxide synthase immunohistochemistry labelled the same neurons a...

NMDA receptors (NMDARs) are key players of synaptic transmission and plasticity, which are localized at synaptic but also extrasynaptic sites. Their activation requires the binding of glutamate and of a second (co)-agonist, glycine and/or D-serine. However, the respective contribution of these two amino acids in controlling NMDAR activity is unclea...

Glial cells are increasingly recognized as active players that profoundly influence neuronal synaptic transmission by specialized signaling pathways. In particular, astrocytes have been shown recently to release small molecules, such as the amino acids l-glutamate and d-serine as "gliotransmitters," which directly control the efficacy of adjacent s...