Dysfunction Of Glutamate System Research Articles

Prenatal Hypoxia Induces Premature Aging Accompanied by Impaired Function of the Glutamatergic System in Rat Hippocampus.

Prenatal hypoxia is among leading causes of progressive brain pathologies in postnatal life. This study aimed to analyze the characteristics of the hippocampal glutamatergic system and behavior of rats in early (2weeks), adult (3months) and advanced (18months) postnatal ontogenesis after exposure to prenatal severe hypoxia (PSH, 180Torr, 5% O2, 3h) during the critical period in the formation of the hippocampus (days 14-16 of gestation). We have shown an age-dependent progressive decrease in the hippocampal glutamate levels, a decrease of the neuronal cell number in the CA1 hippocampal region, as well as impairment of spatial long-term memory in the Morris water navigation task. The gradual decrease of glutamate was accompanied by decreased expression of the genes that mediate glutamate metabolism and recycling in the hippocampus. That deficiency apparently correlated with an increase of the metabotropic glutamate receptor type 1 (mGluR1) and synaptophysin expression. Generation of the lipid peroxidation products in the hippocampus of adult rats subjected to prenatal severe hypoxia (PSH rats) was not increased compared to the control animals when tested in a model of glutamate excitotoxicity induced by severe hypoxia. This demonstrates that excessive glutamate sensitivity in PSH rats does not compensate for glutamate deficiency. Our results show a significant contribution of the glutamate system dysfunction to age-associated decrease of this mediator, cognitive decline, and early neuronal loss in PSH rats.

Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1.

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal–PFC connectivity. Altered hippocampal–PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1–PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity.

Translational psychiatry--light at the end of the tunnel.

Neuroscience has made tremendous progress delineating the cellular and molecular processes important for understanding neuronal development and behavior, but this knowledge has been slow to translate to new treatments for psychiatric illness. To accelerate this transfer of knowledge to the human condition requires the wide-scale adoption of biomarkers that can bridge preclinical and clinical discoveries, and serve as surrogate measures of efficacy before commencing expensive phase III studies. Several biomarker methodologies, including imaging, electroencephalography (EEG), and blood transcriptomics/proteomics, are now showing promise. From an industry perspective, we highlight the utility of quantitative EEG as one example of a translatable biomarker applicable to psychiatric drug development and discuss recent insights into glutamate system dysfunction in schizophrenia and depression gained through translational studies of the drug ketamine.

Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate levels and neurocognition in non-smoking, active alcoholics

BackgroundWe studied the effects of single nucleotide polymorphisms (SNPs) in the metabotropic glutamate receptor 3 (GRM3) gene on brain N-acetylaspartate (NAA) concentrations and executive function (EF) skills in non-smoking, active alcoholics, and evaluated associations between these variables.MethodsSNPs (rs6465084, rs1468412, and rs2299225) in GRM3 were genotyped in 49 male, non-smoking, alcohol-dependent patients and 45 healthy control subjects using ligase detection reactions. NAA/creatine (Cr) ratios in left prefrontal gray matter (GM) and white matter (WM), left parietal GM, left parietal WM, and cerebellar vermis regions were measured by Proton 1 H Magnetic resonance spectroscopy (MRS). EF was measured by the Wisconsin Card Sorting Test (WCST).ResultsCompared to controls, alcoholics had lower NAA/Cr ratios in prefrontal GM and WM regions and performed more poorly on all EF tests (P < 0.001). Alcoholics with the A/A genotype for SNP rs6465084 had lower NAA/Cr ratios in prefrontal GM and WM regions and had poorer EF skills than alcoholics who were G-carriers for this SNP (P < 0.01). Non-alcoholics with the A/A genotype for rs6465084 also had lower NAA/Cr levels in prefrontal GM and made more random errors in the WCST than G-carriers (P < 0.01). The A/A genotype group for SNP rs6465084 was significantly different from the G carriers for the variables of NAA/Cr ratios and WCST scores in both alcoholics and controls (P < 0.05). Alcoholics who were T-carriers for rs1468412 had lower NAA/Cr ratios in prefrontal GM and showed poorer EF skills (P < 0.05). No effects of rs2299225 genotype on NAA/Cr or executive skills were observed. NAA/Cr in left prefrontal regions correlated with certain parameters of EF testing in both alcoholics and controls (P < 0.05), but the significance of this correlation among alcoholics disappeared after adjustment for the effects of genotype.ConclusionsOur results provide evidence that glutamate system dysfunction may play a role in the prefrontal functional abnormalities seen in alcohol dependence. It is possible that certain GRM3 SNP genotypes (the A/A genotype of rs6465084 and the T allele of rs1468412) may further lower NAA/Cr levels and EF skills in addition to the effect of alcohol.

Oral glycine administration increases brain glycine/creatine ratios in men: A proton magnetic resonance spectroscopy study

Oral high-dose glycine administration has been used as an adjuvant treatment for schizophrenia to enhance glutamate neurotransmission and mitigate glutamate system hypofunction thought to contribute to the disorder. Prior studies in schizophrenia subjects documented clinical improvements after 2 weeks of oral glycine administration, suggesting that brain glycine levels are sufficiently elevated to evoke a clinical response within that time frame. However, no human study has reported on brain glycine changes induced by its administration. We utilized a noninvasive proton magnetic resonance spectroscopy ( 1H-MRS) technique termed echo time-averaged (TEAV) 1H-MRS, which permits noninvasive quantification of brain glycine in vivo, to determine whether 2 weeks of oral glycine administration (peak dose of 0.8 g/kg/day) increased brain glycine/creatine (Gly/Cr) ratios in 11 healthy adult men. In scans obtained 17 h after the last glycine dose, brain (Gly/Cr) ratios were significantly increased. The data indicate that it is possible to measure brain glycine changes with proton spectroscopy. Developing a more comprehensive understanding of human brain glycine dynamics may lead to optimized use of glycine site agonists and glycine transporter inhibitors to treat schizophrenia, and possibly to treat other disorders associated with glutamate system dysfunction.

Glutamate Could Play Pivotal Role in Schizophrenia

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessGlutamate Could Play Pivotal Role in SchizophreniaJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:18 Jun 2004https://doi.org/10.1176/pn.39.12.0390030Could the neurotransmitter glutamate, not dopamine, be the major neurotransmitter culprit in schizophrenia? In other words, might glutamate damage the brain and then involve the neurotransmitter dopamine, which has been strongly implicated in schizophrenia?Quite possibly, a study reported in the June American Journal of Psychiatry suggests. Glutamate levels were found to be significantly higher in the brains of teens at high genetic risk for schizophrenia than in the brains of teens not at such risk.The study was headed by Philip Tibbo, M.D., an assistant professor of psychiatry at the University of Alberta in Edmonton, Canada.Tibbo and his coworkers used a technique called 3-T proton magnetic resonance spectroscopy (H-MRS) to measure glutamate levels in the brains of 20 adolescents at high genetic risk for schizophrenia because they had a parent with schizophrenia, as well as in the brains of 22 teens without such genetic risk. The region of the brain chosen for glutamate assessment was the medial prefrontal cortex, because it receives glutamate inputs from the thalamus, as well as from other brain regions that have shown structural abnormalities in schizophrenia.Glutamate levels were found to be significantly higher in the medial prefrontal cortex of the teens at high genetic risk for schizophrenia than in the teens not at such risk.The finding supports the hypothesis that “glutamate system dysfunction may play a role in neuroarchitectural abnormalities seen in schizophrenia...,” Tibbo and his team concluded.These results do not have practical implications for clinical psychiatrists at this time, Tibbo told Psychiatric News. In other words, psychiatrists cannot put teens at genetic risk for schizophrenia in an H-MRS scanner to see whether they have abnormally high levels of glutamate in their brains. However, it may eventually be possible to do so “if techniques improve and [glutamate] correlations are made with cognitive tests,” Tibbo said.In fact, he added, “I am currently writing a manuscript that has results from this same group two years later.... It indicates that changes in glutamate over time correlate with results on cognitive testing.”Still other evidence beside that of Tibbo and his colleagues has been building for the hypothesis that glutamate plays a notable role in schizophrenia. For instance, three proteins are used for reuptake of glutamate by brain neurons. Greater genetic expression for two out of three of the proteins has been found in postmortem thalamus tissue taken from schizophrenia patients than in postmortem thalamus tissue taken from healthy control subjects (Psychiatric News, September 21, 2001).The study was funded by the National Alliance for Research on Schizophrenia and Affective Disorders.The study, “3-T Proton MRS Investigation of Glutamate and Glutamine in Adolescents at High Genetic Risk for Schizophrenia,” is posted online at<http://ajp.psychiatryonline.org/cgi/content/abstract/161/6/1116>.▪ Am J Psychiatry 2004 161 1116 ISSUES NewArchived