Role Of Glutamate Neurotransmission Research Articles

Ampakines - a promising approach to neuroprotection

Increased interest in glutamatergic neurotransmission emerged in the second half of the twentieth century. Later, the role of glutamate neurotransmission in learning and memory processes became clear. AMPA receptors (AMPR) and NMDA receptors (NMDAR) turned out to be important links in the mechanism of long-term potentiation (LTP) involved in memory processes, which was expressed in an increase in the excitatory postsynaptic potential in response to repeated stimuli. The data obtained in recent decades indicate that AMPR is the main regulators of synaptic plasticity, learning and memory. In clinical terms, the greatest interest is not the formation of memory traces in various parts of the brain, but its restoration in various pathological processes, including reactivation of connections between neurons activated by learning in various areas of the brain. AMPAR synaptic plasticity disorder has been detected in several neurodegenerative diseases accompanied by cognitive disorders. Ampakines, a heterogeneous class of numerous small molecules that bind to the allosteric site on the AMPAR receptor, which slows down the kinetics of AMPAR deactivation, enhances excitatory synaptic current and enhances LTP, have become increasingly attracting the attention of researchers.

Survey of NMDA Receptor-related Biomarkers for Depression.

Major depressive disorder (MDD) is an important cause of disability in the world. Depression has negative influences on a person's mental and physical health, quality of life, and functioning. The pathophysiology of depression has not yet been confirmed. The traditional monoamine hypothesis of MDD could not explain the unsatisfactory treatment response of antidepressants. Thus, it is necessary to search other probable pathophysiology of MDD. In recent years, the role of glutamate neurotransmission in depression has drawn much attention. The N-methyl-D-aspartate receptor (NMDAR) is a subclass of glutamate receptors and is implicated in the pathogenesis of MDD and other mental disorders. Furthermore, NMDAR ligands, such as ketamine and Dcycloserine, have shown antidepressive effects in several studies. The diagnosis of MDD depends on physician's subjective evaluation which is often inconsistent. Therefore, reliable objective laboratory biomarkers are essential for more accurate and consistent diagnosis of MDD. In this review, we firstly described the structure and regulation of the NMDAR. We then searched different genes involved in the pathway of glutamatergic neurotransmission and NMDAR, including D-amino acids, glycine, and glutamate. Various related enzymes and transporters that play a role in the modulation of NMDAR neurotransmission were also surveyed. This review aims to investigate NMDAR related metabolism, which may serve as feasible indicators for MDD and may contribute to further exploration of reliable biomarkers for MDD and promote new treatment of depression.

The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission - reviewing the history of the "glutamate inhibition" and "glutamate activation" hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.

Cerebrospinal fluid D-serine concentrations in major depressive disorder negatively correlate with depression severity

BackgroundD-serine is an endogenous co-agonist of N-methyl-D-aspartate receptor (NMDAR) and plays an important role in glutamate neurotransmission. Several studies suggested the possible involvement of D-serine related in the pathophysiology of psychiatric disorders including major depression disorders (MDD). We tried to examine whether cerebrospinal fluid (CSF) or plasma D-serine concentrations are altered in MDD and whether D-serine concentrations correlated with disease severity. Methods26 MDD patients and 27 healthy controls matched for age, sex and ethnicity were enrolled. We measured amino acids in these samples using by high-performance liquid chromatography with fluorometric detection. ResultsD-serine and L-serine, precursor of D-serine, levels in CSF or plasma were not significantly different in patients of MDD compared to controls. Furthermore, a significant correlation between D-serine levels in CSF and Hamilton Depression Rating Scale (HAMD)-17 score was observed (r = −0.65, p = 0.006). Furthermore, we found a positive correlation between CSF D-serine and HVA concentrations in MDD patients (r = 0.54, p = 0.007). CSF D-serine concentrations were correlated with those of plasma in MDD (r = 0.61, p = 0.01) but not in controls. In CSF, we also confirmed a significant correlation between D-serine and L-serine levels in MDD (r = 0.72, p < 0.0001) and controls (r = 0.70, p < 0.0001). ConclusionsThe study has some limitations; sample size was relatively small and most patients were medicated. We revealed that CSF D-serine concentrations were correlated with depression severity and HVA concentrations and further investigation were required to reveal the effect of medication and disease heterogeneity.

Plasma and cerebrospinal fluid G72 protein levels in schizophrenia and major depressive disorder

G72 is a modulator of D-amino acid oxidase, the enzyme that degrades D-serine, an amino acid that plays a critical role in glutamate neurotransmission, and has been implicated in psychiatric disorders. The aim of this study was to examine whether plasma or cerebrospinal fluid (CSF) G72 protein levels were altered in either schizophrenia or major depressive disorder (MDD) and whether any correlation between G72 levels and disease severity existed. Initially, 27 schizophrenic patients, 26 MDD patients, and 27 healthy controls matched for age, sex, and ethnicity were enrolled. Compared to those of controls, plasma or CSF G72 levels were not significantly different in patients with schizophrenia or MDD. Although we found a significant positive correlation between plasma G72 levels and a positive symptoms score on the positive and negative syndrome scale (PANSS), this was not replicated in the second study (40 schizophrenic patients). CSF G72 levels showed no significant correlation with PANSS scores. In MDD, neither plasma nor CSF G72 levels correlated significantly with depression severity. Since severity of our patients were relatively mild, further investigations in a large number of subjects including drug-free patients, younger patients, and more severely affected patients are warranted.

Association of NOS1AP variants and depression phenotypes in schizophrenia

BackgroundThe nitric oxide synthase 1 adaptor protein gene (NOS1AP) has previously been recognised as a schizophrenia susceptibility gene due to its role in glutamate neurotransmission. The gene is believed to inhibit nitric oxide (NO) production activated by the N-methyl-d-aspartate (NMDA) receptor and reduced NO levels have been observed in schizophrenia patients. However, association studies investigating NOS1AP and schizophrenia have produced inconsistent results, most likely because schizophrenia is a clinically heterogeneous disorder. This study aims to investigate the association between NOS1AP variants and defined depression phenotypes of schizophrenia. MethodsNine NOS1AP SNPs, rs1415259, rs1415263, rs1858232, rs386231, rs4531275, rs4656355, rs4657178, rs6683968 and rs6704393 were genotyped in 235 schizophrenia subjects screened for various phenotypes of depression. ResultOne NOS1AP SNP (rs1858232) was associated with the broad diagnosis of schizophrenia and eight SNPs were associated with depression related phenotypes within schizophrenia. The rs1415259 SNP showed strong association with sleep dysregulation phenotypes of depression. ConclusionResults suggest that NOS1AP variants are associated with various forms of depression in schizophrenia and are more prevalent in males. LimitationSchizophrenia is a clinically heterogeneous disease that can vary greatly between different ethnic and geographic populations so our observations should be viewed with caution until they are independently replicated, particularly in larger patient cohorts.

Assessment of glutamine synthetase activity by [13N]ammonia uptake in living rat brain.

Glutamine synthetase (GS) plays an important role in glutamate neurotransmission or neurological disorder in the brain. [(13) N]Ammonia blood flow tracer has been reported to be metabolically trapped in the brain via the glutamate-glutamine pathway. The present study investigated the effect of an inhibitor of GS on [(13) N]ammonia uptake in order to clarify the feasibility of measuring GS activity in the living brain. l-Methionine sulfoximine (MSO), a selective GS inhibitor was microinjected into the ipsilateral striatum in rats. [(13) N]Ammonia uptake was quantified by autoradiography method as well as small animal positron emission tomography (PET) scans. The GS activity of the brain homogenate was assayed from the γ-glutamyl transferase reaction. Autoradiograms showed a decrease of [(13) N]ammonia radioactivity on the MSO-injected side compared with the saline-injected side of the striatum. This reduction could be detected with a small animal PET scanner. MSO had no effect on cerebral blood flow measured by uptake of [(15) O]H2 O. The reduction of [(13) N]ammonia uptake was closely related to the results of GS activity assay. These results indicated that [(13) N]ammonia may enable measurement of GS activity in the living brain.

Olfaxin as a novel Prune2 isoform predominantly expressed in olfactory system

Prune homolog 2 (Drosophila) (PRUNE2) encodes a BCH motif-containing protein that shares homology with the Cayman ataxia-related protein Caytaxin. Caytaxin is a substrate of caspase-3 and is specifically expressed at the presynapse of vesicular-type glutamate transporter (VGLUT)-positive neurons, where it plays a role in glutamate neurotransmission primarily in the cerebellum and hippocampus. Here, we showed that a novel Prune2 isoform contains a BCH motif and localizes predominantly to the synaptic cytosol, similar to Caytaxin. However, the isoform is expressed predominantly in the olfactory bulb and layer Ia of the piriform cortex, where Caytaxin is scarcely expressed. The isoform expression is upregulated during development, similar to that in the presynaptic-localizing proteins Synapsin I and Bassoon. Prune2 and its previously identified isoforms have been shown to be a susceptibility gene for Alzheimer's disease, a biomarker for leiomyosarcomas, a proapoptotic protein, and an antagonist of cellular transformation. In addition, a novel isoform may develop new roles for Prune2 at the synapse in olfactory systems.

Pre‐synaptic glutamate‐induced activation of DA release in the striatum after partial nigral lesion

The present experiments aimed at understanding the functional link between dopamine (DA) and glutamate (GLU) during the compensatory processes taking place after partial DA denervation. Lesion of the lateral part of substantia nigra in rats using 6-hydroxydopamine resulted in DA denervation of the lateral region of the ipsilateral caudate/putamen complex (CPc) whereas the medial CPc was spared. In vivo voltammetry revealed a large increase of extracellular dopamine (DA(ext)) in the medial CPc both ipsilateral and contralateral to the lesion. In addition, in vivo microdialysis and HPLC-ED revealed a concomitant increase of extracellular glutamate (GLU(ext)) in the ipsilateral medial CPc. Post-lesion chronic treatment with the putative neuroprotectors amantadine, memantine, and riluzole counteracted the tonic increases of DA(ext) and GLU(ext), revealing a possible role of GLU neurotransmission in the DA over-expression. Finally, acute low doses of GBR12909 had no effect on the DA(ext) in sham- operated animals, but dramatically increased DA(ext) in lesioned animals. The data suggest that a partial unilateral nigral lesion induces a bilateral increase of DA turn-over in the non-denervated striata through GLU afferences to the DA terminals.

9] Solubilization and reconstitution of synaptic vesicle glutamate transport system

This chapter reviews the solubilization and reconstitution of the vesicular glutamate transport system and describes an extension of these techniques, resulting in a partial purification of the vesicular glutamate transport system and a partial separation of the glutamate transporter and proton-pump ATPase. As these techniques require a minimum of 10–20 mg synaptic vesicle protein, the chapter discusses the synaptic vesicle purification protocol for large-scale preparation of vesicles. The synaptic vesicle glutamate transport system performs a key function in neurotransmission by loading the synaptic vesicle with glutamate. Given its vital role in glutamate neurotransmission, directing glutamate to the neurotransmitter pathway away from the metabolic pathway, it potentially represents an important site of regulation of central nervous system pathogenesis. Synaptic vesicle glutamate transport requires a proton ATPase of the vacuolar type and chloride. These function to provide the appropriate intravesicular pH and electrochemical gradients that are necessary to drive glutamate transport. It is not known whether chloride stimulated, ATP-dependent glutamate transport is accomplished by several proteins, each functioning independently, or if more than one function is performed by one protein.

Immunochemical characterization of brain synaptic membrane glutamate-binding proteins.

Two glutamate-binding proteins (71 and 63 kDa) were previously purified from synaptic plasma membranes (Chen, J.-W., Cunningham, M.D., Galton, V., and Michaelis, E. K. (1988) J. Biol. Chem. 263, 417-426). These proteins may play a role in glutamate neurotransmission in brain. Polyclonal antibodies were raised against the denatured glutamate-binding proteins in rabbits, including sets of antibodies against each of the binding proteins. The antibodies reacted specifically against both 71- and 63-kDa proteins. The antibodies recognized the denatured form of the proteins in Western blots and the native state of the proteins in enzyme-linked immunosorbent assays and in immunoaffinity chromatography and extraction procedures. All antibodies labeled most strongly the 71-kDa protein in Western blots, but extracted both proteins from solubilized synaptic membrane preparations. These findings indicate that the two proteins are closely related immunologically but the reactivity on Western blots differs between these two proteins. Immunoextraction of the 71- and 63-kDa proteins led to a approximately 60% decrease in L-[3H]glutamate-binding activity associated with synaptic membrane proteins. Of the brain subcellular fractions examined, the isolated synaptic plasma membranes had the strongest reaction in enzyme-linked immunosorbent assays toward the antiglutamate-binding protein antisera. Electron microscopy combined with gold particle immunohistochemistry revealed the sites labeled by the antibodies as entities present either on the surface or within the postsynaptic membranes and the associated densities of brain nerve ending particles (synaptosomes). Immunohistochemical procedures of gold labeling with silver enhancement of labeled sites revealed selective neuronal labeling in brain regions enriched in glutamate neurotransmitter pathways such as the hippocampus. Labeling was along dendrites and around cell bodies of pyramidal neurons. Based on the pattern of histochemical labeling, the distribution of immune reactivity in synaptic membranes, and the extractions of a major component of membrane glutamate-recognizing proteins by the antibodies, the glutamate-binding proteins must play a role in glutamate neurotransmission.