Glutamate Hypothesis Research Articles

A systematic meta-analysis of the association of Neuregulin 1 (NRG1), D-amino acid oxidase (DAO), and DAO activator (DAOA)/G72 polymorphisms with schizophrenia.

The glutamate hypothesis of schizophrenia is related to the proposed dysregulation of D-amino acid oxidase (DAO), DAO activator (DAOA)/G72, and Neuregulin 1 (NRG1) genes. Genetic studies have shown significant associations between DAO, DAOA, NRG1 single-nucleotide polymorphisms (SNPs), and schizophrenia. The systematic literature search yielded 6, 5, and 18 new studies for DAO, DAOA, and NRG1 published after 2011 and not included in the previous SchizophreniaGene (SZGene) meta-analysis. We conducted meta-analyses of 20, 23, and 48 case-control studies, respectively, to comprehensively evaluate the association of 8 DAO, 12 DAOA, and 14 NRG1 SNPs with schizophrenia. The updated meta-analyses resulted in the following findings: the C-allele of DAO rs4623951 was associated with schizophrenia across all pooled studies [Odds ratio (OR)=0.88, 95% confidence interval (CI)=0.79-0.98, p=0.02, N=3143]; however, no new reports could be included. The G-allele of DAOA rs778293 was associated with schizophrenia in Asian patients (OR=1.17, 95% CI=1.08-1.27, p=0.00008, N=6117), and the T-allele of DAOA rs3916971 was associated with schizophrenia across all studies (OR=0.84, 95% CI=0.73-0.96, p=0.01, N=1765). Again, for both SNPs, no new eligible studies were available. After adding new reports, the T-allele of NRG1 SNP8NRG241930 (rs62510682) across all studies (OR=0.95, 95% CI=0.91-0.997, p=0.04, N=22,898) and in Caucasian samples (OR=0.95, 95% CI=0.90-0.99, p=0.03, N=16,014), and the C-allele of NRG1 rs10503929 across all studies (OR=0.89, 95% CI=0.81-0.97, p=0.01, N=6844) and in Caucasian samples (OR=0.89, 95% CI=0.81-0.98, p=0.01, N=6414) were protective against schizophrenia. Our systematic meta-analysis is the most updated one for the association of DAO, DAOA, and NRG1 SNPs with schizophrenia.

To Test Glutamate Hypothesis for Schizophrenia Utilizing Proton Magnetic Resonance Spectroscopy

Recent advancement in magnetic resonance spectroscopy (MRS) has elucidated the pathophysiology of mental illness, including schizophrenia. MRS is a neuroimaging technique that non-invasively measures chemicals, using nuclear magnetic resonance. This narrative review explains proton MRS (¹H-MRS) and introduces pivotal studies to examine a glutamate hypothesis for schizophrenia, employing ¹H-MRS.

An examination of the roles of glutamate and sex in latent inhibition: Relevance to the glutamate hypothesis of schizophrenia?

The present study examined the effects of the glutamate receptor antagonist MK-801, the glutamate receptor agonist N-methyl-D-aspartate (NMDA), and sexual dimorphism on latent inhibition to elucidate the glutamate hypothesis of schizophrenia. During the pre-exposure phase, 56 male and 65 female Wistar rats were intracerebroventricularly administered normal saline, MK-801 or NMDA, in the left ventricle and then exposed to a passive avoidance box (or a different context) in three trials over 3 days. Then, all of the rats were placed in the light compartment of the passive avoidance box and were allowed to enter the dark compartment, where they each received a footshock (1mA, 2s) in five trials over 5 days. Injections of the glutamate drugs NMDA and MK-801 did not affect latent inhibition. Sexual dimorphism did not occur in latent inhibition. The present data on the male rats indicated that the glutamate system did not affect latent inhibition, indicating that the glutamate system was not like the dopamine system in terms of mediating the positive symptoms of schizophrenia. The glutamate system might be involved in the negative and cognitive symptoms of schizophrenia. The results may provide information for novel treatments of the negative and cognitive symptoms of schizophrenia.

Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial.

The "glutamate hypothesis of schizophrenia" has changed attitudes in the development of new medications. This study aimed to evaluate the effects of 20mg of memantine per day (as a NMDA receptor antagonist) added to risperidone among male patients with schizophrenia. In a randomized placebo-controlled, double-blind clinical trial, 46 adult male patients with schizophrenia were evaluated in both intervention and control groups at weeks 0, 6 and 12. The positive and negative symptoms scale and the mini mental status examination were used to assess positive, negative and cognitive symptoms and general psychopathology. The mean age of the patients was 44.8 for the intervention group and 45.3 for the control group, and the mean times since diagnosis were 23.5 and 25.7 years in the intervention and the control group, respectively. Positive and general psychopathologic symptoms showed no significant differences between the two groups at baseline or after treatment; while negative symptoms improved significantly in the intervention group at week 12. Cognitive function was also significantly improved in the intervention group at weeks 6 and 12. Memantine is supported as an effective adjunct treatment to improve negative and cognitive symptoms in patients with schizophrenia.

Evidence on the key role of the metabotrobic glutamatergic receptors in the pathogenesis of schizophrenia: a "breakthrough" in pharmacological treatment

The metabotropic glutamate receptors (mGluRs) are expressed pre- and post synaptically throughout the nervous system where they serve as modulators of synaptic transmission and neuronal excitability. The glutamatergic system is involved in a wide range of physiological processes in the brain, and its dysfunction plays an important role in the etiology and pathophysiology of psychiatric disorders, including schizophrenia. This paper reviews the neurodevelopmental origin and genetic susceptibility of schizophrenia relevant to NMDA receptor neurotransmission, and discusses the relationship between NMDA hypofunction and different domains of symptom in schizophrenia as well as putative treatment modality for the disorder. mGlu receptors have been hypothesizes as attractive therapeutic targets for the development of novel interventions for psychiatric disorders. Group II of mGlu receptors are of particular interest because of their unique distribution and the regulatory roles they have in neurotransmission. The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.

Multiple D2 heteroreceptor complexes: new targets for treatment of schizophrenia.

The dopamine (DA) neuron system most relevant for schizophrenia is the meso-limbic-cortical DA system inter alia densely innervating subcortical limbic regions. The field of dopamine D2 receptors and schizophrenia changed markedly with the discovery of many types of D2 heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum. The results indicate that the D2 is a hub receptor which interacts not only with many other G protein-coupled receptors (GPCRs) including DA isoreceptors but also with ion-channel receptors, receptor tyrosine kinases, scaffolding proteins and DA transporters. Disturbances in several of these D2 heteroreceptor complexes may contribute to the development of schizophrenia through changes in the balance of diverse D2 homo- and heteroreceptor complexes mediating the DA signal, especially to the ventral striato-pallidal γ-aminobutyric acid (GABA) pathway. This will have consequences for the control of this pathway of the glutamate drive to the prefrontal cortex via the mediodorsal thalamic nucleus which can contribute to psychotic processes. Agonist activation of the A2A protomer in the A2A-D2 heteroreceptor complex inhibits D2 Gi/o mediated signaling but increases the D2 β-arrestin2 mediated signaling. Through this allosteric receptor-receptor interaction, the A2A agonist becomes a biased inhibitory modulator of the Gi/o mediated D2 signaling, which may the main mechanism for its atypical antipsychotic properties especially linked to the limbic A2A-D2 heterocomplexes. The DA and glutamate hypotheses of schizophrenia come together in the signal integration in D2-N-methyl-d-aspartate (NMDA) and A2A-D2-metabotropic glutamate receptor 5 (mGlu5) heteroreceptor complexes, especially in the ventral striatum. 5-Hydroxytryptamine 2A (5-HT2A)-D2 heteroreceptor complexes are special targets for atypical antipsychotics with high potency to block their 5-HT2A protomer signaling in view of the potential development of pathological allosteric facilitatory 5-HT2A-D2 interaction increasing D2 protomer signaling. Neurotensin (NTS1)-D2 heterocomplexes also exist in the ventral and dorsal striatum, and likely also in midbrain DA nerve cells as NTS1-D2 autoreceptor complexes where neurotensin produces antipsychotic and propsychotic actions, respectively.

MGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner.

Growing evidence indicates that drugs of abuse gain control over the individual by usurping glutamate-linked mechanisms of neuroplasticity in reward-related brain regions. Accordingly, we have shown that glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activity in the amygdala is required for the positive reinforcing effects of alcohol, which underlie the initial stages of addiction. It is unknown, however, if enhanced AMPAR activity in the amygdala facilitates alcohol self-administration, which is a kernel premise of glutamate hypotheses of addiction. Here, we show that low-dose alcohol (0.6 g/kg/30 minutes) self-administration increases phosphorylation (activation) of AMPAR subtype GluA1 S831 (pGluA1 S831) in the central amygdala (CeA), basolateral amygdala and nucleus accumbens core (AcbC) of selectively bred alcohol-preferring P-rats as compared with behavior-matched (non-drug) sucrose controls. The functional role of enhanced AMPAR activity was assessed via site-specific infusion of the AMPAR positive modulator, aniracetam, in the CeA and AcbC prior to alcohol self-administration. Intra-CeA aniracetam increased alcohol-reinforced but not sucrose-reinforced responding and was ineffective following intra-AcbC infusion. Because GluA1 S831 is a Ca2+/calmodulin-dependent protein kinase II (CaMKII) substrate, we sought to determine if AMPAR regulation of enhanced alcohol self-administration is dependent on CaMKII activity. Intra-CeA infusion of the cell-permeable CaMKII peptide inhibitor myristolated autocamtide-2-related inhibitory peptide (m-AIP) dose-dependently reduced alcohol self-administration. A subthreshold dose of m-AIP also blocked the aniracetam-induced escalation of alcohol self-administration, demonstrating that AMPAR-mediated potentiation of alcohol reinforcement requires CaMKII activity in the amygdala. Enhanced activity of plasticity-linked AMPAR-CaMKII signaling in the amygdala may promote escalated alcohol use via increased positive reinforcement during the initial stages of addiction.

PKC GAMMA-MEDIATED SIGNALING AND SCHIZOPHRENIA

Schizophrenia is a complicated mental disorder. Although multiple hypotheses have been proposed to interpret the molecular mechanisms underlying the pathogenesis of the disease, the key pathological process is yet blurry. Early clinical studies have implicated a role of the histidine triad nucleotide-binding protein-1 (Hint1) in the pathogenesis of schizophrenia. A most recent investigation by Zhang et al has defined the activity of protein PKC gamma (PKC𝛾) in the brain using Hint1-knockout animal model. Their finding that Hint1-deficiency causes a compromised PKC𝛾 signaling in the brain may shed a new light on the glutamate hypothesis of schizophrenia.

Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there is no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation.

SNARE Complex Dysfunction: A Unifying Hypothesis for Schizophrenia

Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the world’s population at tremendous personal, social, and economic costs. Individuals with schizophrenia exhibit diverse combinations of positive, negative, and cognitive symptoms. Genetic susceptibility and environmental stressors are major risk factors for schizophrenia, contributing to the variety of phenotypes. It has been widely hypothesized that deficiencies in neurotransmitter systems contribute to schizophrenia. The dopamine hypothesis was supported by observations that pharmacologically increasing dopamine (e.g., with amphetamine) can induce psychosis in humans, whereas antipsychotics that block dopamine alleviate the positive symptoms of schizophrenia. Similarly, the glutamate hypothesis arose from observations that schizophrenia was associated with decreased glutamate levels, and the administration of glutamate antagonists in healthy subjects induced psychosis. These two hypotheses are combined in a third hypothesis, the synaptic hypothesis, which proposes that general deficits in synaptic function are a root cause of schizophrenia ( 1 Johnson R.D. Oliver P.L. Davies K.E. SNARE proteins and schizophrenia: Linking synaptic and neurodevelopmental hypotheses. Acta Biochim Pol. 2008; 55: 619-628 PubMed Google Scholar ). In this issue of Biological Psychiatry, Ramos-Miguel et al. ( 2 Ramos-Miguel A. Beasley C.L. Dwork A.J. Mann J.J. Rosoklija G. Barr A.M. et al. Increased SNARE protein-protein interactions in orbitofrontal and anterior cingulate cortices in schizophrenia. Biol Psychiatry. 2015; 78: 361-373 Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar ) explore the hypothesis that presynaptic abnormalities in the neurotransmitter exocytic machinery are altered in schizophrenia. This hypothesis is intriguing because altered neurotransmitter release could yield problems with dopamine and glutamate signaling, synapse function, and neural development, all of which have been observed in individuals with schizophrenia. Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in SchizophreniaBiological PsychiatryVol. 78Issue 6PreviewSynaptic dysfunction in schizophrenia may be associated with abnormal expression or function of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin, synaptosomal-associated protein 25 [SNAP25], vesicle-associated membrane protein [VAMP]) forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2, and synaptotagmin in brains from autopsies of individuals with and without schizophrenia. Full-Text PDF

Association of NEDD4 gene polymorphisms with schizophrenia and its clinical characteristics in Chinese Han population

To assess the association of neural precursor cell expressed developmentally down-regulated 4 (NEDD4) with schizophrenia. Five single nucleotide polymorphisms (SNPs) of the NEDD4 gene were genotyped by TaqMan SNP genotyping assay in an independent sample of 464 individuals with schizophrenia and 487 healthy controls from eastern Han Chinese population. Clinical data were collected with a general information questionnaire and Positive and Negative Syndrome Scale (PANSS). Frequencies of rs3088077 (allelic: χ2=18.024, P=0.000; genotypic: χ2=16.634, P=0.000), rs7162435 (allelic: χ2=6.771, P=0.009; genotypic: χ2=7.352, P=0.025) and rs2303579 (allelic: χ2=11.253, P=0.001; genotypic: χ2=12.248, P=0.002) were found to be significant different between the two groups. Moreover, TT of rs7162435 was significantly correlated with scores of factors of excitement and hostility (14.53±3.925, F=3.551, P=0.029). rs3088077, rs7162435 and rs2303579 of the NEDD4 gene may be associated with schizophrenia. Moreover, the TT genotype of rs7162435 may increase the severity of excitement and hostility. Our results may provide a clue for delineating the connection between the glutamate hypothesis of schizophrenia and ubiquitination.

Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release. Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification. We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects. The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain.

Role of Spreading Depression On Memory Consolidation in Developmental Animal Model of Schizophrenia

Background Schizophrenia is a complex disorder, characterized by both genetic and environmental factors and their interactions. Post weaning social isolation (SI) has been proposed as a model of Schizophrenia. Glutamate hypothesis in schizophrenia produce analogous symptoms. In this regards, reduction in NMDA receptor activity has been hypothesized for induction of schizophrenia in clinical studies. Furthermore, NMDA receptors activation play role in various neurodegenerative diseases including phenomenon of spreading depression (SD). SD plays a pivotal role in glutamate release and its action on the NMDA receptor. Method and material In the present study 24Wistar juvenile rats (65-80 gr) were used. Animals were classified in three groups as SD treated with Social isolation, social isolation, and sham groups. SI was induced by six week post weaning social isolation of puppies, which followed by four consecutive weeks SD induction in SD-social isolation group. Prepulse inhibition (PPI) test and passive avoidance by shuttle box test have been done at the end of experiment. Results Our result from behavioral test suggested that SD induction during for week after six week social isolation may be able to help to ameliorate schizophrenia symptoms. Significant changes in cognition tests were seen in SD induced group in comparison with social isolation group. Conclusion data from present study revealed that glutamate level in extracellular space which followed by NMDA receptor activation as well as its expression following SD induction perhaps decrease some neurological characteristics of schizophrenia, which could reveal NMDA protective role on schizophrenic patient.

Glutamate and dopamine in schizophrenia: an update for the 21st century.

The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed.

Markers of glutamate signaling in cerebrospinal fluid and serum from patients with bipolar disorder and healthy controls

Glutamate is the major excitatory neurotransmitter in the brain. Aberrations in glutamate signaling have been linked to the pathophysiology of mood disorders. Increased plasma levels of glutamate as well as higher glutamine+glutamate levels in the brain have been demonstrated in patients with bipolar disorder as compared to healthy controls. In this study, we explored the glutamate hypothesis of bipolar disorder by examining peripheral and central levels of amino acids related to glutamate signaling. A total of 215 patients with bipolar disorder and 112 healthy controls from the Swedish St. Göran bipolar project were included in this study. Glutamate, glutamine, glycine, l-serine and d-serine levels were determined in serum and in cerebrospinal fluid using high performance liquid chromatography with fluorescence detection. Serum levels of glutamine, glycine and d-serine were significantly higher whereas l-serine levels were lower in patients with bipolar disorder as compared to controls. No differences between the patient and control group in amino acid levels were observed in cerebrospinal fluid. The observed differences in serum amino acid levels may be interpreted as a systemic aberration in amino acid metabolism that affects several amino acids related to glutamate signaling.

The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies.

A number of studies have indicated that antagonists of the N-methyl-d-aspartate subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings have led to the glutamate hypothesis of schizophrenia. Here we review the evidence for this hypothesis in postmortem studies of brain tissue from individuals affected by schizophrenia, summarizing studies of glutamate neuron morphology, of expression of glutamate receptors and transporters, and of the synthesizing and metabolizing enzymes for glutamate and its co-agonists. We found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex of subjects with schizophrenia and of reduced levels of the axon bouton marker synaptophysin. There were no consistent alterations of mRNA expression of glutamate receptors, although there has been limited study of the corresponding proteins. Studies of the glutamate metabolic pathway have been limited, although there is some evidence that excitatory amino acid transporter-2, glutamine synthetase, and glutaminase have altered expression in schizophrenia. Future studies would benefit from additional direct examination of glutamatergic proteins. Further advances, such as selective testing of synaptic microdomains, cortical layers, and neuronal subtypes, may also be required to elucidate the nature of glutamate signaling impairments in schizophrenia.

The glutamate hypothesis in ALS: pathophysiology and drug development.

Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the major causes are better defined, drug development is directed at downstream pathophysiological mechanisms, themselves incompletely understood. For nearly 30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for ALS. Following the achievement of the riluzole trials, numerous other agents with similar mechanisms have been tested without success. This article provides an overview of excitotoxicity in ALS, focusing on the events that contribute to excess glutamate, how the excess might damage nerve cells, and how this information is being harnessed in the development of potential new neuroprotective agents. The work highlights clinical trials of drugs that have targeted the glutamate system, comments on the potential role of glutamate as a biomarker and concludes with a section on future directions for the field. As research uncovers elusive etiologies and brings clarity to pathophysiological mechanisms, the success of new interventions will increasingly depend on the design of agents that target particular mechanisms for specific individuals. The heady future of personalized drug regimens for ALS rests with medicinal chemists, the scientists whose ideas and work produce these designer drugs.

The glutamate hypothesis of schizophrenia

For many years, the dopamine hypothesis of schizophrenia has been the leading theory explaining the aetiology of schizophrenia. However, since the first observation showed that NMDA-receptor antagonists (e. g., PCP) can induce all kinds of schizophrenia symptoms in humans, the glutamate hypothesis of schizophrenia has been established as an additional explanation model. Apart from the PCP-induced psychoses, many other findings from all areas of modern neuroscience have confirmed and extended the glutamate hypothesis. This review discusses the available evidence for the glutamate hypothesis and puts the different findings into relation. Consecutively, the possibilities for a pharmacological modulation of the glutamate system and recent clinical trials are discussed. To sum up, one could note that the glutamate hypothesis of schizophrenia is now well-established. The development of glutamatergic antipsychotics is still in the early stages, but there is hope for a new generation of antipsychotics based on the glutamate hypothesis of schizophrenia. However, recent findings from registration trials could not provide positive findings for the recently developed glutamatergic drugs.

Antibodies to Surface Dopamine-2 Receptor and N-Methyl-D-Aspartate Receptor in the First Episode of Acute Psychosis in Children

BackgroundThe dopamine and glutamate hypotheses are well known in psychosis. Recently, the detection of autoantibodies against proteins expressed on the surface of cells in the central nervous system has raised the possibility that specific immune-mediated mechanisms may define a biological subgroup within psychosis, although no cohort of a first episode of psychosis in children has been investigated. MethodsSerum taken during the acute presentation of 43 children with first episode of psychosis and serum from 43 pediatric control subjects was assessed for the presence of immunoglobulin (Ig)G, IgM, or IgA antibodies to dopamine-2 receptor (D2R) and NR1 subunit of the N-methyl-D-aspartate receptor using a flow cytometry live cell-based assay and immunolabeling of murine primary neurons. ResultsUsing a cutoff of three SD above the control mean, serum antibodies to D2R or NR1 were detected in 8 of 43 psychotic patients but not detected in any of 43 control subjects (p < .001). Positive immunoglobulin binding to D2R was found in 3 of 43 psychosis patients (3 IgG, 1 IgM, 0 IgA) and to N-methyl-D-aspartate receptor in 6 of 43 patients (5 IgG, 1 IgM, 1 IgA). Specificity of antibody was confirmed by immunoaffinity purification and immunoabsorption. Significant differences in antibody binding to live, fixed, and fixed and permeabilized neurons were observed, confirming that only live cells can define surface epitope immunolabeling. ConclusionsThis is the first report of serum antibodies to surface D2R and NR1 in pediatric patients with isolated psychosis, which supports the hypothesis that a subgroup of patients may be immune-mediated.