glutaminase and Schizophrenia

Glutamate and dopamine hypotheses are leading theories of the pathophysiology of schizophrenia. Multiple lines of evidence suggest that dopaminergic and glutamatergic dysfunction is an underlying mechanism in schizophrenia. Since currently available antipsychotic drugs have significant untoward side effects, identification of new neuroprotective compounds from the medicinal plants may prove beneficial in neurodegenerative disorders. In our previous investigation we have isolated, characterized and reported a novel bioactive compound viz. 3-(3, 4-dimethoxy phenyl)-1-(4-methoxy phenyl) prop-2-en-1-one from the Celastrus paniculatus (CP) is used for the current clinical intervention of schizophrenia disease. The present study is mainly aimed to evaluate the neuroprotective potential of the above bioactive compound against ketamine-induced schizophrenia with particular reference to glutamate metabolism using in vivo and in silico methods. The decrease in glutamine content and the activity levels of glutamate dehydrogenase, glutamine synthetase, and glutaminase in different regions of the rat brain suggests lowered oxidative deamination and lowered mobilization of glutamate towards glutamine formation during ketamine-induced schizophrenia. Pre-treatment with the plant compound reversed the alterations in glutamate metabolism and restored the normal glutamatergic neurotransmission akin to the reference drug, clozapine. In addition, the compound has shown strong interaction and exhibited the highest binding energies against selected NMDA receptors with the lowest inhibition constant than the reference drug. Recoveries of these parameters during anti-schizophrenic treatment suggest that administration of plant compound might offer neuroprotection by interrupting the pathological cascade of glutamatergic neurotransmission that occurs during schizophrenia.

Topics: Animals; Antipsychotic Agents; Brain; Celastrus; Flavonoids; Glutamate Dehydrogenase; Glutamate-Ammonia Ligase; Glutaminase; Glutamine; Ketamine; Male; Molecular Docking Simulation; Neuroprotective Agents; Rats, Wistar; Schizophrenia

Glutaminase-deficient mice (GLS1 hets), with reduced glutamate recycling, have a focal reduction in hippocampal activity, mainly in CA1, and manifest behavioral and neurochemical phenotypes suggestive of schizophrenia resilience. To address the basis for the hippocampal hypoactivity, we examined synaptic plastic mechanisms and glutamate receptor expression. Although baseline synaptic strength was unaffected in Schaffer collateral inputs to CA1, we found that long-term potentiation was attenuated. In wild-type (WT) mice, GLS1 gene expression was highest in the hippocampus and cortex, where it was reduced by about 50% in GLS1 hets. In other brain regions with lower WT GLS1 gene expression, there were no genotypic reductions. In adult GLS1 hets, NMDA receptor NR1 subunit gene expression was reduced, but not AMPA receptor GluR1 subunit gene expression. In contrast, juvenile GLS1 hets showed no reductions in NR1 gene expression. In concert with this, adult GLS1 hets showed a deficit in hippocampal-dependent contextual fear conditioning, whereas juvenile GLS1 hets did not. These alterations in glutamatergic synaptic function may partly explain the hippocampal hypoactivity seen in the GLS1 hets. The maturity-onset reduction in NR1 gene expression and in contextual learning supports the premise that glutaminase inhibition in adulthood should prove therapeutic in schizophrenia.

Topics: Age Factors; Animals; Conditioning, Psychological; Fear; Female; Gene Expression; Glutamic Acid; Glutaminase; Hippocampus; Inhibition, Psychological; Long-Term Potentiation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Synapses; Synaptic Transmission

We describe here a coordinated brain imaging and animal models approach in which we have shown that the hippocampal CA1 region is a principal node in schizophrenia pathogenesis and have identified a novel treatment approach to the disorder based on inhibition of glutamate release. To identify biomarkers, we have focused on the putative prodromal period, typically lasting a few years, preceding the first onset of psychosis. About one-third of a high-risk cohort followed prospectively for 2.5 years will progress to threshold psychosis, making it possible to perform a relatively short prospective study. We have utilized a technological development in functional imaging techniques in which we measure cerebral blood volume (CBV), which allows for interrogation of subregions of the brain in the basal state at submillimeter resolution. Measurements of CBV in schizophrenia as well as in high-risk or prodromal stages can then pinpoint brain subregions differentially targeted during the earliest stages of the disorder. Our data suggest that the CA1 subfield of the hippocampal formation is most consistently implicated across disease stages, identifying a putative biomarker suitable for guiding drug development. Our studies in transgenic mice mutant in the glutamate synthetic enzyme glutaminase support the hypothesis that CA1 hyperfunction is due to altered glutamatergic neurotransmission. As a proof of principle, the glutaminase-deficient mice suggest that pharmacotherapies that reduce glutamatergic neurotransmission in the CA1 subfield may be a uniquely effective therapeutic strategy in schizophrenia and preventative in prodromal stages of the disorder.

Topics: Animals; Blood Volume; CA1 Region, Hippocampal; Cerebrovascular Circulation; Disease Models, Animal; Drug Discovery; Glutamic Acid; Glutaminase; Humans; Image Enhancement; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Mice; Mice, Transgenic; Nerve Net; Psychotropic Drugs; Receptors, Glutamate; Schizophrenia; Synaptic Transmission

Disturbed glutamatergic neurotransmission has become recognized as a key component in the pathophysiology of schizophrenia. The change in serum/plasma glutamate with the use of antipsychotic medication has been studied and may be a possible clinical marker. In the present study, we examined plasma glutamate concentration, including a comprehensive investigation of its involvement with clinical course of schizophrenia and a genomic analysis. We performed a case-control genetic association analysis of the glutaminase 1 (GLS) and 2 (GLS2) genes. In addition, the difference in plasma glutamate concentration between the "acute stage" and "remission stage", and the effect of genotypes of SNPs within the two genes were assessed. The genetic association analysis of the GLS and GLS2 genes showed no association with schizophrenia. Plasma glutamate was increased with antipsychotic medication at "remission stage". Although GLS and GLS2 are not likely genetic risk factors for schizophrenia, changes in plasma glutamate concentration might be connected with clinical course of schizophrenia.

Topics: Adult; Antipsychotic Agents; DNA; Female; Genotype; Glutamic Acid; Glutaminase; Haplotypes; Humans; Isoenzymes; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Schizophrenia

Numerous molecules enable the handling of glutamate that is destined for neurotransmitter release, including transporters, receptors and glutamatergic enzymes. Previous work in our lab has shown altered levels of transcript expression of excitatory amino acid transporters and a vesicular glutamate transporter in the thalamus in schizophrenia. These changes suggest that molecules that facilitate the release and reuptake of glutamate may be abnormal in schizophrenia. In this study we determined the levels of expression of phosphate activated glutaminase (PAG), which converts glutamine to glutamate, and glutamine synthetase (GS), which converts glutamate to glutamine, with the hypothesis that thalamic PAG and GS transcript expression is altered in schizophrenia. We investigated expression of PAG and GS mRNA using in situ hybridization in six different thalamic nuclei (anterior, dorsomedial, centromedial, ventral anterior, ventral and reticular) from 13 persons with schizophrenia and 8 comparison subjects and found that transcripts for PAG and GS were significantly increased in schizophrenia. Increased PAG and GS transcripts suggest enhanced glutamatergic neurotransmission in the thalamus and its efferent targets in schizophrenia.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Female; Glutamate-Ammonia Ligase; Glutaminase; Humans; In Situ Hybridization; Male; Middle Aged; RNA, Messenger; Schizophrenia; Thalamus; Transcription, Genetic

Pharmacological, clinical, and postmortem studies suggest altered gamma-aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects.. Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal nonpsychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase.. Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences. Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged.. Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.

Topics: Age Factors; Aged; Citrate (si)-Synthase; Female; Functional Laterality; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Glutamic Acid; Glutaminase; Humans; Male; Postmortem Changes; Prefrontal Cortex; Schizophrenia; Synaptic Transmission

There is strong evidence for the involvement of the neurotransmitter glutamate system in the pathogenesis of Alzheimer's disease and schizophrenia. In these mental diseases, the brain shows changes in the levels of glutamate and in the function and expression of its transporters and receptors. Since the levels of glutamate are largely determined by the rate of its metabolism, the changes of its concentrations may be associated with dysfunctions of appropriate enzymes. Actually, disturbances of glutamate metabolic enzymes, such as glutaminase, glutamate decarboxylase, and glutamine synthetase were detected in the brain of patients with Alzheimer's disease. The alterations in the expression of glutamine synthetase, glutamine synthetase-like protein, and three isoenzymes of glutamate dehydrogenase in the frontal cortex of patients with schizophrenia suggest that there are impaired glutamate metabolism in this mental disease and Alzheimer's disease.

Topics: Alzheimer Disease; Autopsy; Brain; Frontal Lobe; Glutamate Decarboxylase; Glutamate Dehydrogenase; Glutamate-Ammonia Ligase; Glutamates; Glutaminase; Humans; Schizophrenia