Evidence for glutamatergic neuronal dysfunction in the prefrontal cortex in chronic but not in first-episode patients with schizophrenia: a proton magnetic resonance spectroscopy study.
ABSTRACT Based upon pharmacological challenge and postmortem studies, schizophrenia has been hypothesized to be caused by decreased glutamatergic neurotransmission. We investigated the glutamatergic neuronal metabolism of the dorsolateral prefrontal cortex with localized 1H magnetic resonance spectroscopy in 18 first-episode patients, 21 chronic patients with schizophrenia, and 21 age-matched controls. Chronic patients had significantly lower levels of glutamate/glutamine (Glx) and N-acetylaspartate (NAA) compared to healthy controls and first-episode patients. Reduced metabolite levels were not correlated with duration of illness or medication. Our results indicate glutamatergic dysfunction in chronic schizophrenia that could be evidence of a progressive brain disorder.
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ABSTRACT: Over the last 50 years, evidence for central involvement of glutamatergic neurotransmission in the pathophysiology of schizophrenia has accumulated. Recent advances in neuroimaging technology now allow several components of glutamatergic neurotransmission to be assessed in the living human brain. Positron emission tomography (PET) or single photon emission tomography (SPET) in combination with select radiotracers allows visualization of glutamatergic receptors in vivo, and magnetic resonance (MR) - based techniques allow mapping of the effects of glutamatergic agents on regional brain activation, and the measurement of regional glutamate concentrations. These imaging studies have provided evidence for regional glutamatergic abnormalities in psychosis, and are beginning to describe both the evolution of these abnormalities over the course of the illness and their response to therapeutic intervention. In parallel, advances in small animal imaging and the development of animal models have provided a platform to explore the neuropathological consequences of glutamatergic abnormality, and the potential antipsychotic efficacy of novel compounds. The molecular diversity of the glutamatergic system has driven the design of several compounds targeting aspects of glutamatergic transmission, and clinical trials have yielded encouraging results. Here, we review the contribution of imaging studies to date in understanding glutamatergic abnormalities in psychosis, and discuss the potential of new glutamatergic compounds for treatment of the disorder.Current pharmaceutical biotechnology 01/2012; 13(8):1500-12. DOI:10.2174/138920112800784961 · 2.51 Impact Factor
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ABSTRACT: Evidence has accumulated over the past years that dysregulation of glutamatergic neurotransmission maybe implicated in the pathophysiology of schizophrenia. Glutamate acts on two major classes of receptors: ionotropic receptors, which are ligand-gated ion channels, and metabotropic receptors (mGluRs), coupled to heterotrimeric G-proteins. Although several pharmacological evidences point to abnormal glutamatergic transmission in schizophrenia, changes in the expression of glutamatergic receptors in the prefrontal cortex of patients with schizophrenia remains equivocal. In the present work, we have investigated glutamatergic neurotransmission in schizophrenia by assessing the expression in Brodmann Area 10 of mGluR5, the AMPA receptor subunits GluR1 and GluR2, and Na(+)/K(+) ATPase-α1, a potential modulator of glutamate uptake in the brain. Semiquantitative analysis of the expression of these proteins from postmortem brains revealed a particularly prominent reduction of GluR1 and GluR2 expression in patients with schizophrenia vs the control group. Conversely, we observed an up-regulation in the levels of Na(+)/K(+) ATPase-α1 expression. Finally, no change in the protein levels of mGluR5 was observed in schizophrenia. Our findings support and expand the hypothesis of glutamatergic dysfunction in prefrontal cortex in the pathophysiology of schizophrenia.Schizophrenia Research 02/2011; 128(1-3):7-14. DOI:10.1016/j.schres.2011.01.021 · 4.43 Impact Factor
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ABSTRACT: A progressive post-onset decrease in gray matter volume 1.5 years after first hospitalization in schizophrenia has been shown in superior temporal gyrus (STG). However, it is still controversial whether progressive volume reduction occurs in chronic schizophrenia in the STG and amygdala-hippocampal complex (AHC), structures found to be abnormal in chronic schizophrenia. These structures were measured at two time points in 16 chronic schizophrenia patients and 20 normal comparison subjects using manual tracing with high spatial resolution magnetic resonance imaging (MRI). Average interscan interval was 3.1 years for schizophrenia patients and 1.4 years for healthy comparison subjects. Cross-sectional comparisons showed smaller relative volumes in schizophrenia compared with controls in posterior STG and AHC. An ANCOVA with interscan interval as a covariate showed there was no statistically significant progression of volume reduction in either the STG or AHC in the schizophrenia group compared with normal subjects. In the schizophrenia group, volume change in the left anterior AHC significantly correlated with PANSS negative symptoms. These data, and separately reported first episode data from our laboratory, suggest marked progression at the initial stage of schizophrenia, but less in chronic schizophrenia.Schizophrenia Research 07/2009; 113(1):84-94. DOI:10.1016/j.schres.2009.05.004 · 4.43 Impact Factor