Glutamate Hypothesis Research Articles

A role for endothelial NMDA receptors in the pathophysiology of schizophrenia

Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.

Solute Carrier Family 1 (SLC1A1) Contributes to Susceptibility and Psychopathology Symptoms of Schizophrenia in the Han Chinese Population.

ObjectiveSchizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamate hypothesis describes one possible pathogenesis of SZ. The solute carrier family 1 gene (SLC1A1) is one of several genes thought to play a critical role in regulating the glutamatergic system and is strongly implicated in the pathophysiology of SZ. In this study, we identify polymorphisms of the SLC1A1 gene that may confer susceptibility to SZ in the Han Chinese population.MethodsWe genotyped 36 single-nucleotide polymorphisms (SNPs) using Illumina GoldenGate assays on a BeadStation 500G Genotyping System in 528 paranoid SZ patients and 528 healthy controls. Psychopathology was rated by the Positive and Negative Symptom Scale.ResultsSignificant associations were found in genotype and allele frequencies for SNPs rs10815017 (p = 0.002, 0.030, respectively) and rs2026828 (p = 0.020, 0.005, respectively) between SZ and healthy controls. There were significant associations in genotype frequency at rs6476875 (p = 0.020) and rs7024664 (p = 0.021) and allele frequency at rs3780412 (p = 0.026) and rs10974573 (p = 0.047) between SZ and healthy controls. Meanwhile, significant differences were found in genotype frequency at rs10815017 (p = 0.015), rs2026828 (p = 0.011), and rs3780411 (p = 0.040) in males, and rs7021569 in females (p = 0.020) between cases and controls when subdivided by gender. Also, significant differences were found in allele frequency at rs2026828 (p = 0.003), and rs7021569 (p = 0.045) in males, and rs10974619 in females (p = 0.044). However, those associations disappeared after Bonferroni’s correction (p’s > 0.05). Significant associations were found in the frequencies of four haplotypes (AA, CA, AGA, and GG) between SZ and healthy controls (χ 2 = 3.974, 7.433, 4.699, 4.526, p = 0.046, 0.006, 0.030, 0.033, respectively). There were significant associations between rs7032326 genotypes and PANSS total, positive symptoms, negative symptoms, and general psychopathology in SZ (p = 0.002, 0.011, 0.028, 0.008, respectively).ConclusionThe present study provides further evidence that SLC1A1 may be not a susceptibility gene for SZ. However, the genetic variations of SLC1A1 may affect psychopathology symptoms.

Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis.

In the past years, several theories have been advanced to explain the pathogenesis of Major Depressive Disorder (MDD), a neuropsychiatric disease that causes disability in general population. Several theories have been proposed to define the MDD pathophysiology such as the classic “monoamine-theory” or the “glutamate hypothesis.” All these theories have been recently integrated by evidence highlighting inflammation as a pivotal player in developing depressive symptoms. Proinflammatory cytokines have been indeed claimed to contribute to stress-induced mood disturbances and to major depression, indicating a widespread role of classical mediators of inflammation in emotional control. Moreover, during systemic inflammatory diseases, peripherally released cytokines circulate in the blood, reach the brain and cause anxiety, anhedonia, social withdrawal, fatigue, and sleep disturbances. Accordingly, chronic inflammatory disorders, such as the inflammatory autoimmune disease multiple sclerosis (MS), have been associated to higher risk of MDD, in comparison with overall population. Importantly, in both MS patients and in its experimental mouse model, Experimental Autoimmune Encephalomyelitis (EAE), the notion that depressive symptoms are reactive epiphenomenon to the MS pathology has been recently challenged by the evidence of their early manifestation, even before the onset of the disease. Furthermore, in association to such mood disturbance, inflammatory-dependent synaptic dysfunctions in several areas of MS/EAE brain have been observed independently of brain lesions and demyelination. This evidence suggests that a fine interplay between the immune and nervous systems can have a huge impact on several neurological functions, including depressive symptoms, in different pathological conditions. The aim of the present review is to shed light on common traits between MDD and MS, by looking at inflammatory-dependent synaptic alterations associated with depression in both diseases.

Changes in subunit composition of NMDA receptors in animal models of schizophrenia by repeated administration of methamphetamine

The dopamine and glutamate hypotheses reflect only some of the pathophysiological changes associated with schizophrenia. We have proposed a new “comprehensive progressive pathophysiology model” based on the “dopamine to glutamate hypothesis.” Repeated administration of methamphetamine (METH) at a dose of 2.5 mg/kg in rats has been used to assess dynamic changes in the pathophysiology of schizophrenia. Previous use of this model suggested N-methyl-d-aspartate receptor (NMDA-R) dysfunction, but the mechanism could only be inferred from limited, indirect observations. In the present study, we used this model to investigate changes in the expression of NMDA-R subunits. Repeated administration of METH significantly decreased the gene expression levels of glutamate ionotropic receptor NMDA type subunit (Grin) subtypes Grin1 and Grin2c in the prefrontal cortex (PFC), Grin1 and Grin2a in the hippocampus (HPC), and Grin1, Grin2b, and Grin2d in the striatum (ST).We observed a significant difference in Grin1 expression between the PFC and ST. Furthermore, repeated administration of METH significantly decreased the protein expression of GluN1 in both cytosolic and synaptosomal fractions isolated from the PFC, and significantly decreased the protein expression of GluN1 in the cytosolic fraction, but not the synaptosomal fraction from the ST. These regional differences may be due to variations in the synthesis of GluN1 or intracellular trafficking events in each area of the brain. Considering that knockdown of Grin1 in mice affects vulnerability to develop schizophrenia, these results suggest that this model reflects some of the pathophysiological changes of schizophrenia, combining both the dopamine and glutamate hypotheses.

S181. ANALYSIS OF THE AMELIORATING EFFECT OF D-SERINE ON GLUN2D DEFICIENT MICE

BackgroundThe glutamate hypothesis of schizophrenia postulates NMDA receptor (NMDAR) hypofunction as a major pathophysiological mechanism based on clinical observations and preclinical evidence. Mice with globally reduced NMDAR expression display hyperlocomotion, sensorimotor gating deficits, cognitive deficits and social withdrawal. NMDARs are tetramers composed of 2 obligatory GluN1 (NR1) and 2 variable GluN2A-D (NR2A-D) subunits. GluN2A and GluN2B are the main cortical NMDAR subunits, but genetic models provided evidence that psychosis-like effects of NMDAR antagonists are mediated by GluN2C/GluN2D subunits. Previous data suggest a role also of the GluN2D subunit in schizophrenia-associated abnormalities [1].MethodsWe aimed to assess a comprehensive behavioural phenotyping of GluN2D deficient mice, including locomotion, affective behaviours and general welfare, but drew special focus on cognitive functions, including spatial learning, short-term and long-term memory, as well as puzzle solving. We further investigated the effect of D-Serine on the GluN2D KO mice. D-Serine is a NMDAR modulator and acts as an agonist at the glycine site. Previous work in clinical trials suggests significant therapeutic effects of D-serine on negative and positive symptoms, cognitive deficits and motor symptoms. We used the chronic application of D-Serin by supplementing it into the drinking water of the subjects.ResultsPreliminary data indicate no effect on locomotor alterations of the GluN2D mice, however a potential improvement in short-term memory and wellbeing-associated parameters. They indicate a role of the GluN2D subunit and a beneficial effect of D-serine on schizophrenia-induced parameters, including physiological, welfare-associated burrowing and cognitive performance in the short term task of the puzzle box test.DiscussionOur preliminary data indicate a role of the GluN2D subunit in the emergence of cognitive deficits associated with schizophrenia and a potential therapeutic effect of D-serine in alleviating these deficits. Further investigations are planned to further validate these findings.ReferenceInta et. al, Neurosci Biobehav Rev, 34(3): 285–94, 2010

AMPA receptor subunit localization in schizophrenia anterior cingulate cortex

The glutamate hypothesis of schizophrenia suggests that altered glutamatergic transmission occurs in this illness, although precise mechanisms of dysregulation remain elusive. AMPA receptors (AMPARs), a subtype of ionotropic glutamate receptor, are the main facilitators of fast, excitatory neurotransmission in the brain, and changes in AMPAR number or composition at synapses can regulate synaptic strength and plasticity. Prior evidence of abnormal expression of transmembrane AMPAR regulatory proteins (TARPs) in schizophrenia suggests defective trafficking of AMPARs, which we propose could lead to altered AMPAR expression at excitatory synapses. To test this hypothesis, we isolated subcellular fractions enriched for endoplasmic reticulum (ER) and synapses from anterior cingulate cortex (ACC) from schizophrenia (N = 18) and comparison (N = 18) subjects, and measured glutamate receptor subunits (GluA1, GluA2, GluA3, GluA4, NR1, NR2A, NR2B, and NR3A) and TARP member γ2 (stargazin) in homogenates and subcellular fractions by western blot analysis. We found decreased expression of stargazin and an increased ratio of GluA2:stargazin in ACC homogenates, while in the synapse fraction we identified a decrease in GluA1 and reduced ratios of GluA1:stargazin and GluA1:GluA2 in schizophrenia. The amount of stargazin in the ER fraction was not different, but the relative amount of ER/Total stargazin was increased in schizophrenia. Together, these findings suggest that associations between stargazin and AMPA subunits are abnormal, potentially affecting forward trafficking or synaptic stability of GluA1-containing AMPARs. These data provide evidence that altered interactions with trafficking proteins may contribute to glutamate dysregulation in schizophrenia.

Modulation of thalamo-cortical activity by the NMDA receptor antagonists ketamine and phencyclidine in the awake freely-moving rat

Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24 h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.

Toward a Glutamate Hypothesis of Frontotemporal Dementia.

Frontotemporal dementia (FTD) is a heterogenous neurodegenerative disorder, characterized by diverse clinical presentations, neuropathological characteristics and underlying genetic causes. Emerging evidence has shown that FTD is characterized by a series of changes in several neurotransmitter systems, including serotonin, dopamine, GABA and, above all, glutamate. Indeed, several studies have now provided preclinical and clinical evidence that glutamate is key in the pathogenesis of FTD. Animal models of FTD have shown a selective hypofunction in N-methyl D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, while in patients, glutamatergic pyramidal neurons are depleted in several areas, including the frontal and temporal cortices. Recently, a selective involvement of the AMPA GluA3 subunit has been observed in patients with autoimmune anti-GluA3 antibodies, which accounted for nearly 25% of FTD patients, leading to a decrease of the GluA3 subunit synaptic localization of the AMPA receptor and loss of dendritic spines. Other in vivo evidence of the involvement of the glutamatergic system in FTD derives from non-invasive brain stimulation studies using transcranial magnetic stimulation, in which specific stimulation protocols have indirectly identified a selective and prominent impairment in glutamatergic circuits in patients with both sporadic and genetic FTD. In view of limited disease modifying therapies to slow or revert disease progression in FTD, an important approach could consist in targeting the neurotransmitter deficits, similarly to what has been achieved in Parkinson’s disease with dopaminergic therapy or Alzheimer’s disease with cholinergic therapy. In this review, we summarize the current evidence concerning the involvement of the glutamatergic system in FTD, suggesting the development of new therapeutic strategies.

Glutamate hypothesis in schizophrenia

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual's life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter-century, an abundance of evidence from pharmacologic challenges, post-mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N-methyl-d-aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment-resistant symptoms, which account for persistent disability.

Astrocytic Regulation of Glutamate Transmission in Schizophrenia.

According to the glutamate hypothesis of schizophrenia, the abnormality of glutamate transmission induced by hypofunction of NMDA receptors (NMDARs) is causally associated with the positive and negative symptoms of schizophrenia. However, the underlying mechanisms responsible for the changes in glutamate transmission in schizophrenia are not fully understood. Astrocytes, the major regulatory glia in the brain, modulate not only glutamate metabolism but also glutamate transmission. Here we review the recent progress in understanding the role of astrocytes in schizophrenia. We focus on the astrocytic mechanisms of (i) glutamate synthesis via the glutamate-glutamine cycle, (ii) glutamate clearance by excitatory amino acid transporters (EAATs), (iii) D-serine release to activate NMDARs, and (iv) glutamatergic target engagement biomarkers. Abnormality in these processes is highly correlated with schizophrenia phenotypes. These findings will shed light upon further investigation of pathogenesis as well as improvement of biomarkers and therapies for schizophrenia.

Role of copper in depression. Relationship with ketamine treatment

Depression is one of the most common psychiatric issues with a proportion of adults with major depressive disorder who fail to achieve remission with index pharmacological treatment. There are unmet needs in ADT focus on non-monoaminergic agents. Accumulating evidence suggests that the N-Methyl-d-aspartate receptor (NMDAR) plays an important role in the neurobiology and treatment of major depressive disorder. The role of copper ions in pathogenesis and treatment of depression is not fully clarified, however interaction between copper and NMDAR is of prime importance. Release of copper ions inhibits NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function thus protects neurons from glutamatergic excitotoxity. Abnormalities in glutamatergic transmission are the key of glutamate hypothesis of depression. Some authors revealed that NMDARs are also regulated by cellular prion protein (PrPC) and indicated that interactions of copper, glycine and NMDARs subunits are vital for the regulation of the receptor. As NMDAR antagonist ketamine is known to produce rapid antidepressive effect, observation of copper serum levels in patients treated with ketamine may provide important information about connections between NMDAR antagonistic agents and trace elements antagonistic to that receptor. It is necessary to carry out further studies related to copper and ketamine in depression treatment.

DARK Classics in Chemical Neuroscience: Phencyclidine (PCP).

Phencyclidine (PCP, "angel dust", an arylcyclohexylamine) was the first non-natural, man-made illicit drug of abuse, and was coined 'the most dangerous drug in America" in the late 1970s (amidst sensational horror stories of the drug's effects); however, few other illicit drugs have had such a significant and broad impact on society-both good and bad. Originally developed as a new class of anesthetic, PCP-derived psychosis gave way to the PCP hypothesis of schizophrenia (later coined the NMDA receptor hypofunction hypothesis or the glutamate hypothesis of schizophrenia), which continues to drive therapeutic discovery for schizophrenia today. PCP also led to the discovery of ketamine (and a new paradigm for the treatment of major depression), as well as other illicit, designer drugs, such as methoxetamine (MXE) and a new wave of Internet commerce for illicit drugs (sold as research chemicals, or RCs). Furthermore, PCP is a significant contaminant/additive of many illegal drugs sold today, due to its ease of preparation by clandestine chemists. Here, we will review the history, importance, synthesis (both legal and clandestine), pharmacology, drug metabolism, and folklore of PCP, a true DARK classic in chemical neuroscience.

Ketamine for Treatment-Resistant Depression: a New Advocate.

Current alternatives for the treatment of major depressive disorder lack efficacy and have a delayed onset of action. Recently, the glutamatergic neurotransmission system has been noted to play an important role in the pathophysiology of this disorder. Ever since the first report of the antidepressant effects of the N-methyl-D-aspartate receptor antagonist, ketamine, research has been redirected to novel therapeutic targets. With this rapidly growing evidence of a fast-acting antidepressant such as ketamine, as well as its efficacy in treatment-resistant cases of depression, off-label use has become popular in certain settings. In this article, the clinical antidepressant properties of ketamine in relation to the glutamate hypothesis of depression are discussed, to highlight the breakthrough of these findings in the development of novel therapeutic strategies and provide a clearer view of its benefits and potential harms.

S231. THE ROLE OF DOPAMINERGIC AND GLUTAMATERGIC NEUROTRANSMISSION IN DELUSIONAL IDEATION AND SENSORY INFORMATION PROCESSING OF PATIENTS WITH SCHIZOPHRENIA IN COMPARISON TO HEALTHY HUMAN PARTICIPANTS

BackgroundThe primary aim of this study was to generate neurobiological evidence regarding the impact of dopaminergic and glutamatergic neurotransmission on reasoning biases related to delusional ideation in patients with schizophrenia associated with impaired processing of sensory information. The proposed respective roles of these neurotransmitter systems have been encapsulated in the so-called dopamine- and glutamate-hypotheses of schizophrenia. From a behavioural perspective both reduced glutamate and enhanced dopamine levels are currently discussed as critical contributing factors to generate aberrant beliefs (glutamate) during information sampling and to generate confidence or expected precision (dopamine) during action selection. Hence, by modulating levels of glutamate and dopamine in the brain we hypothesized to induce reported impairments of patients with schizophrenia related todelusional ideation.MethodsThe study consisted of three aligned experiments: In the first two experiments a prospective interventional drug study was conducted with n=192 participants employing a randomized, placebo-controlled, double-blinded design on two parallel testing-groups, receiving either dopaminergic or glutamatergic neuromodulators: Experiment I: either 2.5mg haloperidol (D1/D2-receptor antagonist; HAL), 2.5mg bromocriptine (D2-receptor agonist; BRO), or placebo (PLC-1). Experiment II: either 120mg Dextromethorphan (NMDA-receptor antagonist, DXM), 250mg D-Cycloserine (NMDA-receptor agonist, CYC), or placebo (PLC-2). In the third experiment n=45 patients with schizophrenia (SZ) and n=45 healthy control participants (HC) matched for gender, age and IQ were investigated. All experiments employed a computerized (Matlab, Cogent) version of the Beadstask (Huq, Garety et al. 1988). In total participants processes 60 Beadstask trials subdivided into three levels of difficulty: (I) easy trials with a bias of 80–90% for one predominant bead color in a sequence, (II) difficult trials (60–70% bias), and (III) ambiguous trials (no bias, 50% likelihood). Additionally, the task consisted of three parts that were presented in a fixed order: an easy draws-to-decision condition, an easy probability estimates condition, and a difficult draws-to-decision condition.ResultsIn accordance with foregoing studies, SZ patients showed significantly less draws to decision compared to HC (all p≤0.038). Explorative analysis across experimental conditions further revealed no significant differences for participants receiving DXM (NMDA-receptor antagonist) compared SZ patients (all p≥0.090), but obtained less draws to decision in the DXM group than all other groups. Whereas following HAL intervention the number of draws increased significantly compared to any other experimental group (all p≤0.048). Analyzing the probability estimates condition we quantified changes of probability estimates on an individual subject level whenever there was a change of bead color in a sequence (so called disconfirmatory evidence score, DES). In case of easy and difficult trial types we observed significantly higher DES scores in participants with SZ compared to HC (p≤0.003) and again obtained no differences between SZ and DXM (p=0.037).DiscussionOur findings are supportive for a hypothesized relationship between neurotransmitter state alterations of glutamate and dopamine in patients with schizophrenia and the delusional ideation. Future analysis will focus on developing a computational behavioral model of cognitive processing of the Beadstask, implementing our neurobiological findings in order to further disentangle the neurobiological underpinnings of delusional ideation in patients with schizophrenia.

F184. TESTING THE GABA-GLUTAMATE HYPOTHESIS FOR SCHIZOPHRENIA IN RELATION TO AUDITORY HALLUCINATIONS - PRELIMINARY RESULTS

BackgroundThe gamma-aminobutyric acid (GABA)-glutamate hypothesis of schizophrenia suggests a neurotransmitter imbalance – reduced GABA and increased glutamate - which causes disruption of the modulation between inhibitory GABAergic interneurons and excitatory glutamatergic neurons. In the left superior temporal gyrus (STG) both hyperactivation and increased glutamate levels have previously been associated with auditory hallucinations in schizophrenia patients. However, the STG GABA-glutamate imbalance by simultaneously measuring GABA and glutamate in the same subjects has not previously been tested, and was therefore the aim of the present study. We hypothesized reduced GABA and increased glutamate in the patients relative to controls. Furthermore, reduced GABA and elevated glutamate in STG should be related to severity of auditory hallucinations in these patients.MethodsThe current study tested 23 schizophrenia patients (18 hallucinating and 5 non-hallucinating) and 53 healthy controls. The sample included both female and male participants above the age of 18. All patients were on medication, and they were tested at different times relative to the treatment onset. Magnetic resonance spectroscopy (MRS) was used to acquire data from voxels in the right and left superior temporal gyrus (Heschl’s gyri) with a 3T GE 750 Discovery MR scanner. PRESS and MEGA-PRESS sequences were applied to measure glutamate and GABA, respectively. Voxel tissue water was used as reference for glutamate and GABA. Scores on the Positive and Negative Syndrome Scale (PANSS) were also collected, and used to differentiate hallucinating from non-hallucinating patients.ResultsSeparate 2(Group) x 2(Hemisphere) ANOVAs were estimated for GABA and glutamate. No main or interaction effects came out significant for GABA (All F(1,73)<2.7, p>0.1, η2<0.03). The analysis for glutamate resulted in a main effect of Hemisphere (F(1,74)=24, p<0.001, η2=0.25) in which the right STG showed overall higher concentrations than the left STG. In addition, an interaction effect between Group and Hemisphere was found (F(1,74)=5.22, p=0.03, η2=0.07). Bonferroni Post-hoc analysis showed significantly elevated glutamate levels in patients relative to controls in the right STG only (p=0.005). Furthermore, a multiple regression analysis was estimated between severity of hallucinations (PANSS P3 item) at the time of testing, and GABA and glutamate values in left and right STG. Although the overall model fit was non-significant, an approximate significant correlation was found between hallucination severity and left STG glutamate levels (β=0.36, t=2.1, SE=0.17, p=0.05).DiscussionThe present study found higher glutamate levels in schizophrenia patients relative to healthy controls in the right STG. In spite of no overall differences in glutamate in the left STG, as initially hypothesized, glutamate levels in this region was found to predict severity of auditory hallucinations. One could speculate that the additional neuronal activity associated with auditory hallucinations elevate glutamate to ‘normal levels’ corresponding to that of healthy controls. The increased glutamate levels in the right STG seems (linearly) unrelated to auditory hallucinations and future analysis should test whether other symptoms are related to this finding. Overall, the study found only limited support for the GABA-glutamate hypothesis; In spite of increased glutamate in one of the regions, GABA was not found to be reduced in patients and was unrelated to auditory hallucinations.

Effects of N-Methyl-D-aspartate (NMDA) antagonists ketamine, methoxetamine, and phencyclidine on the odor span test of working memory in rats.

The glutamate hypothesis proposes that N-Methyl-D-aspartate (NMDA) receptor hypofunction underlies cognitive and perhaps other schizophrenic symptoms. The present study used the odor span task to assess the effects of NMDA antagonists on remembering multiple stimuli in rodents. This task uses an incrementing nonmatching-to-sample procedure in which responses to a new olfactory stimulus are reinforced on each trial, whereas responses to previously presented stimuli are not. NMDA antagonists have been associated with memory impairments in a variety of animal models; however, there are inconsistencies across different NMDA antagonists and tasks used. The current study compared the acute effects of phencyclidine (PCP), ketamine (KET), and the novel NMDA antagonist methoxetamine (MXE) on responding in the odor span task and a simple discrimination control task. PCP and MXE impaired odor span accuracy at doses that did not impair simple discrimination in most rats; however, the effects of KET were less selective. Within-session analyses indicated that the effects of PCP and MXE depended on the number of stimuli to remember, that is, impairment only occurred when the memory load was relatively high. These effects of PCP and MXE were consistent with the hypothesis that NMDA antagonists may interfere with working memory, but the basis for less selective results with KET are unclear. (PsycINFO Database Record

Schizophrenia: An overview

Schizophrenia is a serious mental disorder that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality. They may hear voices other people don’t hear. Schizophrenia symptoms contain three categories; Positive, Negative and Cognitive. There are different causes of Schizophrenia this may be due to Genes, Environment or Change in Brain Structures. Due to Schizophrenia the illness occurs in less than 1 percent of the general population, but this range becomes 10 percent who have first degree relatives with the disorder, such as parents, Brother or sister. Most people with schizophrenia are not violent; however, the risk of violence is greatest when schizophrenia is untreated. There are different molecular mechanisms of Schizophrenia i.e. Neurodevelopment Hypothesis, Dopamine hypothesis and Glutamate Hypothesis. It is important to help a person with schizophrenia symptoms get treatment as quickly as possible. Here Two main types of treatment can help with symptoms: antipsychotic medications and psychosocial treatments. Family and friends can help their loved ones with schizophrenia by helping them get treatment and encouraging them to stay in treatment.

D-serine Measurements in Brain Slices or Other Tissue Explants.

D-serine is an atypical amino acid present in the mammalian body (most amino acids in the mammalian body are L-isomers) that is mostly known in neuroscience for its role as a co-agonist controlling the N-methyl D-aspartate receptor (NMDAR). D-serine levels are decreased in patients with schizophrenia and this is thought to mediate, at least in part, the hypofunction of NMDARs that is central to the glutamate hypothesis for the etiology of this neuropsychiatric disorder. D-serine detection was first established using high performance liquid chromatography, a costly and complex technique that requires high levels of expertise. But with the increasing interest in this unconventional amino acid, there is an increasing need for easier, cheaper and more accessible detection methods. Here we describe the amperometric, biosensor-based method we employed in a recent publication (Papouin et al., 2017b). It allows reliable measurement of D-serine levels from fresh tissue, such as acute brain slices, for concentrations higher than 100 nM, with minimal technical requirements.

Prediction Analysis for Transition to Schizophrenia in Individuals at Clinical High Risk for Psychosis: The Relationship of DAO, DAOA, and NRG1 Variants with Negative Symptoms and Cognitive Deficits.

Schizophrenia is characterized by positive and negative symptoms and cognitive dysfunction. The glutamate hypothesis of schizophrenia has been hypothesized to explain the negative symptoms and cognitive deficits better than the dopamine hypothesis alone. Therefore, we aimed to evaluate whether glutamatergic variants such as d-amino acid oxidase (DAO), DAO activator (DAOA)/G72, and neuregulin 1 (NRG1) single-nucleotide polymorphisms (SNPs) and their mRNA levels predicted (i) transition to schizophrenia spectrum disorders and (ii) research domain criteria (RDoC) domains, mainly negative valence and cognitive systems. In a 3-year prospective study cohort of 185 individuals (age: 13–35 years) at high risk and ultra-high risk (UHR) for psychosis, we assessed DAO (rs3918347, rs4623951), DAOA (rs778293, rs3916971, rs746187), and NRG1 (rs10503929) SNPs and their mRNA expression. Furthermore, we investigated their association with RDoC domains, mainly negative valence (e.g., anxiety, hopelessness) and cognitive (e.g., perception disturbances, disorganized symptoms) systems. NRG1 rs10503929 CC + CT versus TT genotype carriers experienced significantly more disorganized symptoms. DAOA rs746187 CC versus CT + TT genotype, DAOA rs3916971 TT versus TC + CC genotype, and DAO rs3918347 GA + AA versus GG genotype carriers experienced nominally more hopelessness, visual perception disturbances, and auditory perception disturbances, respectively. The schizophrenia risk G-allele of DAO rs3918347 nominally increased risk for those UHR individuals with attenuated positive symptoms syndrome. No association between DAO, DAOA, NRG1 SNPs, and conversion to schizophrenia spectrum disorders was observed. Our findings suggest that DAO, DAOA, and NRG1 polymorphisms might influence both RDoC negative valence and cognitive systems, but not transition to schizophrenia spectrum disorders.

Controversial Effects of D-Amino Acid Oxidase Activator (DAOA)/G72 on D-Amino Acid Oxidase (DAO) Activity in Human Neuronal, Astrocyte and Kidney Cell Lines: The N-methyl D-aspartate (NMDA) Receptor Hypofunction Point of View.

Dysfunction of D-amino acid oxidase (DAO) and DAO activator (DAOA)/G72 genes have been linked to neuropsychiatric disorders. The glutamate hypothesis of schizophrenia has proposed that increased DAO activity leads to decreased D-serine, which subsequently may lead to N-methyl-D-aspartate (NMDA) receptor hypofunction. It has been shown that DAOA binds to DAO and increases its activity. However, there are also studies showing DAOA decreases DAO activity. Thus, the effect of DAOA on DAO is controversial. We aimed to understand the effect of DAOA on DAO activity in neuron-like (SH-SY5Y), astrocyte-like (1321N1) and kidney-like (HEK293) human cell lines. DAO activity was measured based on the release of hydrogen peroxide and its interaction with Amplex Red reagent. We found that DAOA increases DAO activity only in HEK293 cells, but has no effect on DAO activity in SH-SY5Y and 1321N1 cells. This might be because of different signaling pathways, or due to lower DAO and DAOA expression in SH-SY5Y and 1321N1 cells compared to HEK293 cells, but also due to different compartmentalization of the proteins. The lower DAO and DAOA expression in neuron-like SH-SY5Y and astrocyte-like 1321N1 cells might be due to tightly regulated expression, as previously reported in the human post-mortem brain. Our simulation experiments to demonstrate the interaction between DAOA and human DAO (hDAO) showed that hDAO holoenzyme [hDAO with flavine adenine dinucleotide (FAD)] becomes more flexible and misfolded in the presence of DAOA, whereas DAOA had no effect on hDAO apoprotein (hDAO without FAD), which indicate that DAOA inactivates hDAO holoenzyme. Furthermore, patch-clamp analysis demonstrated no effect of DAOA on NMDA receptor activity in NR1/NR2A HEK293 cells. In summary, the interaction between DAO and DAOA seems to be cell type and its biochemical characteristics dependent which still needs to be elucidated.